JP2009132660A - Composition for treating esophageal cancer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition for treating esophageal cancer having an excellent HGFR (hepatocyte growth factor receptor) inhibitory action. <P>SOLUTION: The composition for treating esophageal cancer includes a compound represented by general formula (I) (wherein R<SP>1</SP>is a 3- to 10-membered nonaromatic heterocyclic group or the like; R<SP>2</SP>and R<SP>3</SP>are each a hydrogen atom; R<SP>4</SP>, R<SP>5</SP>, R<SP>6</SP>and R<SP>7</SP>are each the same or different and a hydrogen atom, a halogen atom, a 1-6C alkyl group or the like; R<SP>8</SP>is a hydrogen atom or the like; R<SP>9</SP>is a 3- to 10-membered nonaromatic heterocyclic group; n is an integer of 1 or 2; and X is a group represented by the formula: -CH= or a nitrogen atom), a salt thereof or a hydrate of them. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to esophageal cancer containing novel pyridine derivatives and pyrimidine derivatives or salts thereof or hydrates thereof having hepatocyte growth factor receptor inhibitory action, antitumor action, angiogenesis inhibitory action, cancer metastasis inhibitory action, etc. It relates to a therapeutic composition.

Hepatocyte growth factor receptor (hereinafter abbreviated as “HGFR”) in various tumors such as pancreatic cancer, stomach cancer, colon cancer, breast cancer, prostate cancer, lung cancer, kidney cancer, brain tumor, ovarian cancer, and esophageal cancer. ) Has been reported (Non-patent Documents 1 and 5). HGFR expressed in these tumor cells is stimulated constitutively or by hepatocyte growth factor (hereinafter abbreviated as “HGF”) to cause tyrosine kinase autophosphorylation in the intracellular region. It is thought to be involved in malignant transformation (abnormal growth, invasion or increased metastatic potential).
In addition, HGFR is also expressed in vascular endothelial cells, and HGF stimulates HGFR and promotes proliferation and migration of vascular endothelial cells, and thus has been reported to be involved in tumor angiogenesis (Non-Patent Document). 2).
Furthermore, it has been reported that NK4, which is an HGF antagonist peptide, suppresses cancer cell invasion and inhibits tumor angiogenesis by blocking the HGF-HGFR signal (Non-patent Documents 3 and 4).
Therefore, a compound having an HGFR inhibitory action is expected to be useful as an antitumor agent, an angiogenesis inhibitor or a cancer metastasis inhibitor.
On the other hand, there is Patent Document 1 as a document disclosing a low molecular compound having an HGFR inhibitory action.

International Publication No. 2007/023768 Pamphlet Oncology Reports, 5, 1013-1024 (1998) Advances in Cancer Research, 67, 257-279 (1995) British Journal of Cancer, 84, 864-873 (2001) Cancer Sci. , 94, 321-327 (2003) Oncogene, 25 (3), 409-418 (2006)

  An object of the present invention is to search for and find a composition for treating esophageal cancer by suppressing HGFR-mediated abnormal cell growth, morphological change, and increased motility in vivo.

  As a result of intensive studies in view of the above circumstances, the present inventors have found that a novel pyridine derivative represented by the following general formula (I) and a pyrimidine derivative or a salt thereof or a hydrate thereof have an excellent HGFR inhibitory action. And the present invention was completed.

（式中、Ｒ^１は、３〜１０員非芳香族ヘテロ環式基（ただし、環を構成する原子中に窒素原子が必ず含まれ、かつ窒素原子から、結合手が出ているものに限る）または式−ＮＲ^１１ａＲ^１１ｂ（式中、Ｒ^１１ａおよびＲ^１１ｂは、同一または異なって、水素原子、Ｃ_１−６アルキル基、Ｃ_３−６アルケニル基、Ｃ_３−６アルキニル基、Ｃ_３−１０シクロアルキル基、Ｃ_６−１０アリール基、５〜１０員へテロアリール基または４〜１０員非芳香族ヘテロ環式基を意味する。ただし、Ｒ^１１ａおよびＲ^１１ｂは、下記置換基群ａまたは下記置換基群ｂから選ばれる置換基を有していてもよい。
［置換基群ａ］
ハロゲン原子、水酸基、メルカプト基、ニトロ基、シアノ基およびオキソ基。
［置換基群ｂ］
Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−６アルキニル基、Ｃ_３−１０シクロアルキル基、Ｃ_６−１０アリール基、５〜１０員ヘテロアリール基、３〜１０員非芳香族ヘテロ環式基、Ｃ_１−６アルコキシ基、Ｃ_３−６アルケニルオキシ基、Ｃ_３−６アルキニルオキシ基、Ｃ_３−１０シクロアルコキシ基、Ｃ_６−１０アリールオキシ基、５〜１０員ヘテロアリールオキシ基、４〜１０員非芳香族ヘテロ環オキシ基、Ｃ_１−６アルキルチオ基、Ｃ_３−６アルケニルチオ基、Ｃ_３−６アルキニルチオ基、Ｃ_３−１０シクロアルキルチオ基、Ｃ_６−１０アリールチオ基、５〜１０員ヘテロアリールチオ基、４〜１０員非芳香族ヘテロ環チオ基および式−Ｔ^１−Ｔ^２−Ｔ^３
(式中、Ｔ^１は、単結合またはＣ_１−６アルキレン基を意味する。
Ｔ^２は、カルボニル基、スルフィニル基、スルホニル基、式−Ｃ（＝Ｏ）−Ｏ−で表される基、式−Ｏ−Ｃ（＝Ｏ）−で表される基、式−ＳＯ_２−Ｏ−で表される基、式−Ｏ−ＳＯ_２−で表される基、式−ＮＲ^Ｔ１−で表される基、式−Ｃ（＝Ｏ）−ＮＲ^Ｔ１−で表される基、式−ＮＲ^Ｔ１−Ｃ（＝Ｏ）−で表される基、式−ＳＯ_２−ＮＲ^Ｔ１−で表される基または式−ＮＲ^Ｔ１−ＳＯ_２−で表される基を意味する。
Ｔ^３は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−６アルケニル基、Ｃ_３−６アルキニル基、Ｃ_３−１０シクロアルキル基、Ｃ_６−１０アリール基、５〜１０員ヘテロアリール基または４〜１０員非芳香族ヘテロ環式基を意味する。
Ｒ^Ｔ１は、水素原子またはＣ_１−６アルキル基を意味する。）で表される基からなり、上記各基は、下記置換基群ｃから選ばれる置換基を有していてもよい。
［置換基群ｃ］
ハロゲン原子、水酸基、メルカプト基、ニトロ基、シアノ基、オキソ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−６アルキニル基、Ｃ_３−１０シクロアルキル基、Ｃ_６−１０アリール基、５〜１０員ヘテロアリール基、３〜１０員非芳香族ヘテロ環式基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルキルチオ基、モノ−Ｃ_１−６アルキルアミノ基およびジ−Ｃ_１−６アルキルアミノ基。）で表される基を意味する。
ただし、Ｒ^１は、上記置換基群ａまたは上記置換基群ｂから選ばれる置換基を有していてもよい。
Ｒ^２およびＲ^３は、水素原子を意味する。
Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、同一または異なって、水素原子、ハロゲン原子、水酸基、シアノ基、トリフルオロメチル基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−６アルキニル基、Ｃ_１−６アルコキシ基、アミノ基、モノ−Ｃ_１−６アルキルアミノ基、ジ−Ｃ_１−６アルキルアミノ基、式−ＣＯ−Ｒ^１２（式中、Ｒ^１２は、水素原子、水酸基、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、アミノ基、モノ−Ｃ_１−６アルキルアミノ基またはジ−Ｃ_１−６アルキルアミノ基を意味する。）で表される基を意味する。
Ｒ^８は、水素原子またはＣ_１−６アルキル基を意味する。
Ｒ^９は、３〜１０員非芳香族ヘテロ環式基（ただし、環を構成する原子中に窒素原子が必ず含まれ、かつ窒素原子から、結合手が出ているものに限る）または式−ＮＲ^１１ａＲ^１１ｂ（式中、Ｒ^１１ａおよびＲ^１１ｂは、上記定義と同意義を意味する）で表される基で表される基を意味する。
ただし、Ｒ^９は、上記置換基群ａまたは上記置換基群ｂから選ばれる置換基を有していてもよい。
ｎは、１ないし２の整数を意味する。
Ｘは、式−Ｃ（Ｒ^１０）＝（式中、Ｒ^１０は、水素原子、ハロゲン原子、シアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−６アルキニル基、式−ＣＯ−Ｒ^１２（式中、Ｒ^１２は、上記定義と同意義を意味する。）で表される基を意味する。）で表される基または窒素原子を意味する。）
で表される化合物もしくはその塩またはそれらの水和物を含有する食道癌治療用組成物。
［２］ Ｒ^１が、上記［１］に記載の置換基群ａまたは置換基群ｂから選ばれる置換基を有していてもよい３〜１０員非芳香族ヘテロ環式基（ただし、環を構成する原子中に窒素原子が必ず含まれ、かつ窒素原子から、結合手が出ているものに限る）である［１］記載の食道癌治療用組成物。
［３］ Ｒ^１が、上記［１］に記載の置換基群ａもしくは置換基群ｂから選ばれる置換基を有していてもよい式

（式中、ａは、１ないし４の整数を意味する。）で表される基または上記［１］に記載の置換基群ａもしくは置換基群ｂから選ばれる置換基を有していてもよい式

（式中、ｂは、１ないし３の整数を意味する。Ｚは、酸素原子、硫黄原子、カルボニル基、スルホニル基または式−ＮＲ^Ｚ−（式中、Ｒ^Ｚは、水素原子またはＣ_１−６アルキル基を意味する。）で表される基を意味する。）で表される基である［１］記載の食道癌治療用組成物。
［４］ Ｒ^１が、下記置換基群ｄから選ばれる置換基を有していてもよいアゼチジン−１−イル基、下記置換基群ｄから選ばれる置換基を有していてもよいピロリジン−１−イル基、下記置換基群ｄから選ばれる置換基を有していてもよいピペリジン−１−イル基、下記置換基群ｄから選ばれる置換基を有していてもよいアゼパン−１−イル基、下記置換基群ｄから選ばれる置換基を有していてもよいピペラジン−１−イル基、下記置換基群ｄから選ばれる置換基を有していてもよいジアゼパン−１−イル基、下記置換基群ｄから選ばれる置換基を有していてもよいモルホリン−４−イル基、下記置換基群ｄから選ばれる置換基を有していてもよいチオモルホリン−４−イル基または下記置換基群ｄから選ばれる置換基を有していてもよい１，１−ジオキソチオモルホリン−４−イル基である［１］記載の食道癌治療用組成物。
［置換基群ｄ］
ハロゲン原子、水酸基、メルカプト基、シアノ基、ホルミル基、オキソ基、Ｃ_１−６アルキル基、Ｃ_３−１０シクロアルキル基、Ｃ_１−６アルコキシ基、アミノ基、モノ−Ｃ_１−６アルキルアミノ基、ジ−Ｃ_１−６アルキルアミノ基、アゼチジニル基、ピロリジニル基、ピペリジニル基、ピペラジニル基、ジアゼパニル基および式−Ｔ^４−Ｔ^５ (式中、Ｔ^４は、カルボニル基またはスルホニル基を意味する。Ｔ^５は、Ｃ_１−６アルキル基、Ｃ_３−１０シクロアルキル基、アゼチジニル基、ピロリジニル基、ピペリジニル基、水酸基、Ｃ_１−６アルコキシ基、アミノ基、モノ−Ｃ_１−６アルキルアミノ基またはジ−Ｃ_１−６アルキルアミノ基を意味する。)で表される基からなり、上記各基は、水酸基、Ｃ_１−６アルキル基、ジ−Ｃ_１−６アルキルアミノ基、アゼチジニル基またはピロリジニル基を有していてもよい。
［５］ Ｒ^１が、下記置換基群ｅから選ばれる置換基を有していてもよいアゼチジン−１−イル基、下記置換基群ｅから選ばれる置換基を有していてもよいピロリジン−１−イル基、下記置換基群ｅから選ばれる置換基を有していてもよいピペリジン−１−イル基、下記置換基群ｅから選ばれる置換基を有していてもよいピペラジン−１−イル基、下記置換基群ｅから選ばれる置換基を有していてもよいジアゼパン−１−イル基または下記置換基群ｅから選ばれる置換基を有していてもよいモルホリン−４−イル基である［１］記載の食道癌治療用組成物。
［置換基群ｅ］
メチル基、エチル基、ジメチルアミノ基、アゼチジニル基、ピロリジニル基、ピペリジニル基およびピペラジニル基からなり、上記各基は、水酸基、メチル基、ジメチルアミノ基、アゼチジニル基、ピロリジニル基またはピペリジニル基を有していてもよい。
［６］ Ｒ^１が、下記置換基群ｇから選ばれる置換基を有していてもよいアゼチジン−１−イル基、下記置換基群ｇから選ばれる置換基を有するピロリジン−１−イル基、下記置換基群ｇから選ばれる置換基を有するピペリジン−１−イル基または下記置換基群ｇから選ばれる置換基を有するピペラジン−１−イル基である［１］記載の食道癌治療用組成物。
［置換基群ｇ］
ジメチルアミノ基、アゼチジニル基、ピロリジニル基、ピペリジニル基、ピペラジニル基、ジメチルアミノメチル基、ジメチルアミノエチル基、アゼチジン−１−イルメチル基、ピロリジン−１−イルメチル基およびピペリジン−１−イルメチル基からなり、上記各基は、メチル基またはジメチルアミノ基を有していてもよい。
［６−１］ Ｒ^１が、下記置換基群ｇ−１から選ばれる置換基を有していてもよいアゼチジン−１−イル基、下記置換基群ｇ−１から選ばれる置換基を有するピロリジン−１−イル基、下記置換基群ｇ−１から選ばれる置換基を有するピペリジン−１−イル基または下記置換基群ｇ−１から選ばれる置換基を有するピペラジン−１−イル基である［１］記載の食道癌治療用組成物。
［置換基群ｇ−１］
アゼチジニル基、ピロリジニル基、ピペリジニル基、ピペラジニル基、ジメチルアミノメチル基、ジメチルアミノエチル基、アゼチジン−１−イルメチル基、ピロリジン−１−イルメチル基およびピペリジン−１−イルメチル基からなり、上記各基は、メチル基またはジメチルアミノ基を有していてもよい。
［６−２］ Ｒ^１が、ジメチルアミノ基を有するアゼチジン−１−イル基、ジメチルアミノ基を有するピロリジン−１−イル基またはジメチルアミノ基を有するピペリジン−１−イル基である［１］記載の食道癌治療用組成物。
［６−３］ Ｒ^１が、下記置換基群ｇ−２から選ばれる置換基を有していてもよいアゼチジン−１−イル基、下記置換基群ｇ−２から選ばれる置換基を有するピロリジン−１−イル基または下記置換基群ｇ−２から選ばれる置換基を有するピペリジン−１−イル基である［１］記載の食道癌治療用組成物。
［置換基群ｇ−２］
水酸基、メトキシ基、ヒドロキシメチル基およびジメチルアミノアセトキシ基。
［６−４］ Ｒ^１が、［２−（ジメチルアミノ）エチル］ピペラジン−１−イル基、４−ピロリジン−１−イルピペリジン−１−イル基、４−［（ジメチルアミノ）メチル］ピペリジン−１−イル基、４−アゼチジン−１−イルピペリジン−１−イル基、４−［３−（ジメチルアミノ）アゼチジン−１−イル］ピペリジン−１−イル基、４−（４−メチルピペラジン−１−イル）ピペリジン−１−イル基、４−（１−メチルピペリジン−４−イル）ピペラジン−１−イル基、４−（１−メチルアゼチジン−３−イル）ピペラジン−１−イル基、４−（ジメチルアミノ）ピペリジン−１−イル基、４−（アゼチジン−１−イルメチル）ピペリジン−１−イル基、４−（ピロリジン−１−イルメチル）ピペリジン−１−イル基、（３Ｓ）−３−（ジメチルアミノ）ピロリジン−１−イル基、（３Ｒ）−３−（ジメチルアミノ）ピロリジン−１−イル基、アゼチジン−１−イル基、ピロリジン−１−イル基、モルホリン−４−イル基、４−メチルピペラジン−１−イル基、３−ヒドロキシアゼチジン−１−イル基、１，３’−ビアゼチジン−１’−イル基、３−（ヒドロキシメチル）アゼチジン−１−イル基、３−（ジメチルアミノ）アゼチジン−１−イル基、３−［（ジメチルアミノ）メチル］アゼチジン−１−イル基、４−ヒドロキシピペリジン−１−イル基、４−（ヒドロキシメチル）ピペリジン−１−イル基、（３Ｒ）−３−ヒドロキシピロリジン−１−イル基、（３Ｓ）−３−ヒドロキシピロリジン−１−イル基、３−（アゼチジン−１−イルメチル）アゼチジン−１−イル基または３−（２−ジメチルアミノアセトキシ）アゼチジン−１−イル基である［１］記載の食道癌治療用組成物。
［７］ Ｒ^１が、式−ＮＲ^１１ａＲ^１１ｂ（式中、Ｒ^１１ａおよびＲ^１１ｂは、上記［１］に記載のＲ^１１ａおよびＲ^１１ｂと同意義を意味する。）で表される基である［１］記載の食道癌治療用組成物。
［８］ Ｒ^１が、式−ＮＲ^１１ｃＲ^１１ｄ（式中、Ｒ^１１ｃは、水素原子またはＣ_１−６アルキル基を意味する。Ｒ^１１ｄは、Ｃ_１−６アルキル基または式

（式中、ｃは、１ないし３の整数を意味する。Ｚ^１は、酸素原子、硫黄原子、カルボニル基、スルホニル基または式−ＮＲ^Ｚ１−（式中、Ｒ^Ｚ１は、水素原子またはＣ_１−６アルキル基を意味する。）で表される基を意味する。）で表される基を意味する。ただし、Ｒ^１１ｄは上記［１］に記載の置換基群ａまたは置換基群ｂから選ばれる置換基を有していてもよい。）で表される基である［１］記載の食道癌治療用組成物。
［９］ Ｒ^１が、式−ＮＲ^１１ｅＲ^１１ｆ（式中、Ｒ^１１ｅは、水素原子またはＣ_１−６アルキル基を意味する。Ｒ^１１ｆは、Ｃ_１−６アルキル基、ピロリジン−３−イル基、ピペリジン−３−イル基、ピペリジン−４−イル基またはテトラヒドロピラン−４−イル基を意味する。ただし、Ｒ^１１ｆは、上記［４］に記載の置換基群ｄから選ばれる置換基を有していてもよい。）で表される基である［１］記載の食道癌治療用組成物。
［１０］ Ｒ^１が、式−ＮＲ^１１ｇＲ^１１ｈ（式中、Ｒ^１１ｇは、水素原子またはメチル基を意味する。Ｒ^１１ｈは、ｎ−プロピル基、ｎ−ブチル基、ピロリジン−３−イル基、ピペリジン−３−イル基、ピペリジン−４−イル基またはテトラヒドロピラン−４−イル基を意味する。ただし、Ｒ^１１ｈは、下記置換基群ｆから選ばれる置換基を有していてもよい。）で表される基である［１］記載の食道癌治療用組成物。
［置換基群ｆ］
メチル基、エチル基、ｎ−プロピル基、アセチル基、ジメチルアミノ基、ジエチルアミノ基、アゼチジニル基、ピロリジニル基およびピペラジニル基からなり、上記各基は、メチル基またはジメチルアミノ基を有していてもよい。
［１１］ Ｒ^１が、式−Ｎ（ＣＨ_３）Ｒ^１１ｉ（式中、Ｒ^１１ｉは、ｎ−プロピル基、ｎ−ブチル基、ピロリジン−３−イル基またはピペリジン−４−イル基を意味する。ただし、Ｒ^１１ｉは、下記置換基群ｈから選ばれる置換基を有する。）で表される基である［１］記載の食道癌治療用組成物。
［置換基群ｈ］
ジメチルアミノ基、ジエチルアミノ基、ジメチルアミノエチル基、ジメチルアミノプロピル基および１−メチルアゼチジン−３−イル基。
［１２］ Ｒ^１が、式−Ｎ（ＣＨ_３）Ｒ^１１ｊ（式中、Ｒ^１１ｊは、１−メチルピペリジン−４−イル基または１−エチルピペリジン−４−イル基を意味する。）で表される基である［１］記載の食道癌治療用組成物。
［１２−１］ Ｒ^１が、式−Ｎ（ＣＨ_３）Ｒ^１１ｋ（式中、Ｒ^１１ｋは、３−（ジメチルアミノ）プロピル基または１−［２−（ジメチルアミノ）エチル］ピペリジン−４−イル基を意味する。）で表される基である［１］記載の食道癌治療用組成物。
［１２−２］ Ｒ^１が、メチル（１−メチルピペリジン−４−イル）アミノ基、（１−エチルピペリジン−４−イル）（メチル）アミノ基、［３−（ジメチルアミノ）プロピル］（メチル）アミノ基または｛１−［２−（ジメチルアミノ）エチル］ピペリジン−４−イル｝（メチル）アミノ基である［１］記載の食道癌治療用組成物。
［１３］ Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７が、同一または異なって、水素原子、ハロゲン原子またはＣ_１−６アルキル基である［１］〜［１２−２］のいずれか１記載の食道癌治療用組成物。
［１４］ Ｒ^８が、水素原子である［１］〜［１３］のいずれか１記載の食道癌治療用組成物。
［１５］ Ｘが、式−Ｃ（Ｒ^１０ａ）＝（式中、Ｒ^１０ａは、水素原子、ハロゲン原子またはシアノ基を意味する。）で表される基である［１］〜［１４］のいずれか１記載の食道癌治療用組成物。
［１６］ Ｘが、窒素原子である［１］〜［１４］のいずれか１記載の食道癌治療用組成物。
［１７］ ｎが、１である［１］〜［１６］のいずれか１記載の食道癌治療用組成物。
［１８］ Ｒ^９が、上記［１］に記載の置換基群ａもしくは置換基群ｂから選ばれる置換基を有していてもよいモノ−Ｃ_１−６アルキルアミノ基、上記［１］に記載の置換基群ａもしくは置換基群ｂから選ばれる置換基を有していてもよいモノ−Ｃ_３−１０シクロアルキルアミノ基、上記［１］に記載の置換基群ａもしくは置換基群ｂから選ばれる置換基を有していてもよいモノ−Ｃ_６−１０アリールアミノ基、上記［１］に記載の置換基群ａもしくは置換基群ｂから選ばれる置換基を有していてもよいモノ−５〜１０員へテロアリールアミノ基または上記［１］に記載の置換基群ａもしくは置換基群ｂから選ばれる置換基を有していてもよいモノ−４〜１０員非芳香族ヘテロ環アミノ基である［１］〜［１７］のいずれか１記載の食道癌治療用組成物。
［１９］ Ｒ^９が、上記［１］に記載の置換基群ａもしくは置換基群ｂから選ばれる置換基を有していてもよいモノ−Ｃ_３−１０シクロアルキルアミノ基または上記［１］に記載の置換基群ａもしくは置換基群ｂから選ばれる置換基を有していてもよいモノ−Ｃ_６−１０アリールアミノ基である［１］〜［１７］のいずれか１記載の食道癌治療用組成物。
［１９−１］ Ｒ^９が、下記置換基群ｉから選ばれる置換基を有していてもよいモノ−Ｃ_３−１０シクロアルキルアミノ基または下記置換基群ｉから選ばれる置換基を有していてもよいモノ−Ｃ_６−１０アリールアミノ基である［１］〜［１７］のいずれか１記載の食道癌治療用組成物。
［置換基群ｉ］
ハロゲン原子、トリフルオロメチル基、シアノ基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基。
［１９−２］ Ｒ^９が、上記［１９−１］に記載の置換基群ｉから選ばれる置換基を有していてもよいシクロペンチルアミノ基、上記［１９−１］に記載の置換基群ｉから選ばれる置換基を有していてもよいシクロヘキシルアミノ基、上記［１９−１］に記載の置換基群ｉから選ばれる置換基を有していてもよいシクロヘプチルアミノ基または上記［１９−１］に記載の置換基群ｉから選ばれる置換基を有していてもよいフェニルアミノ基である［１］〜［１７］のいずれか１記載の食道癌治療用組成物。
［２０］ 一般式（Ｉ）で表される化合物が、
（１）Ｎ−［４−（｛２−［（｛４−［２−（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ｅｔｈｙｌ］ｐｉｐｅｒａｚｉｎ−１−ｙｌ｝ｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）−２−ｆｌｕｏｒｏｐｈｅｎｙｌ］−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［ｍｅｔｈｙｌ（１−ｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ−４−ｙｌ）ａｍｉｎｏ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３）Ｎ−（４−Ｆｌｕｏｒｏｐｈｅｎｙｌ）−Ｎ’−｛２−ｆｌｕｏｒｏ−４−［（２−｛［（４−ｐｙｒｒｏｌｉｄｉｎ−１−ｙｌｐｉｐｅｒｉｄｉｎ−１−ｙｌ）ｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｄｉｎ−４−ｙｌ）ｏｘｙ］ｐｈｅｎｙｌ｝ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（４）Ｎ−［４−（｛２−［（｛４−［（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ｍｅｔｈｙｌ］ｐｉｐｅｒｉｄｉｎ−１−ｙｌ｝ｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）−２−ｆｌｕｏｒｏｐｈｅｎｙｌ］−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（５）Ｎ−｛４−［（２−｛［（４−Ａｚｅｔｉｄｉｎ−１−ｙｌｐｉｐｅｒｉｄｉｎ−１−ｙｌ）ｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｄｉｎ−４−ｙｌ）ｏｘｙ］−２−ｆｌｕｏｒｏｐｈｅｎｙｌ｝−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（６）Ｎ−［４−（｛２−［（｛４−［３−（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ａｚｅｔｉｄｉｎ−１−ｙｌ］ｐｉｐｅｒｉｄｉｎ−１−ｙｌ｝ｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）−２−ｆｌｕｏｒｏｐｈｅｎｙｌ］−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（７）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［４−（４−ｍｅｔｈｙｌｐｉｐｅｒａｚｉｎ−１−ｙｌ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（８）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［４−（１−ｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ−４−ｙｌ）ｐｉｐｅｒａｚｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（９）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［４−（１−ｍｅｔｈｙｌａｚｅｔｉｄｉｎ−３−ｙｌ）ｐｉｐｅｒａｚｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（１０）Ｎ−（４−｛［２−（｛［４−（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝−２−ｆｌｕｏｒｏｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（１１）Ｎ−（４−｛［２−（｛［４−（Ａｚｅｔｉｄｉｎ−１−ｙｌｍｅｔｈｙｌ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝−２−ｆｌｕｏｒｏｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（１２）Ｎ−（４−Ｆｌｕｏｒｏｐｈｅｎｙｌ）−Ｎ’−（２−ｆｌｕｏｒｏ−４−｛［２−（｛［４−（ｐｙｒｒｏｌｉｄｉｎ−１−ｙｌｍｅｔｈｙｌ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（１３）Ｎ−（４−｛［２−（｛［（３Ｓ）−３−（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ｐｙｒｒｏｌｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝−２−ｆｌｕｏｒｏｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（１４）Ｎ−（４−｛［２−（｛［（３Ｒ）−３−（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ｐｙｒｒｏｌｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝−２−ｆｌｕｏｒｏｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（１５）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［ｍｅｔｈｙｌ（１−ｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ−４−ｙｌ）ａｍｉｎｏ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−ｐｈｅｎｙｌｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（１６）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［４−（４−ｍｅｔｈｙｌｐｉｐｅｒａｚｉｎ−１−ｙｌ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−ｐｈｅｎｙｌｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（１７）Ｎ−［４−（｛２−［（｛４−［３−（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ａｚｅｔｉｄｉｎ−１−ｙｌ］ｐｉｐｅｒｉｄｉｎ−１−ｙｌ｝ｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）−２−ｆｌｕｏｒｏｐｈｅｎｙｌ］−Ｎ’−ｐｈｅｎｙｌｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（１８）Ｎ−（４−｛［２−（｛［（１−Ｅｔｈｙｌｐｉｐｅｒｉｄｉｎ−４−ｙｌ）（ｍｅｔｈｙｌ）ａｍｉｎｏ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝−２−ｆｌｕｏｒｏｐｈｅｎｙｌ）−Ｎ’−ｐｈｅｎｙｌｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（１９）Ｎ−［４−（｛２−［（Ａｚｅｔｉｄｉｎ−１−ｙｌｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）−２−ｆｌｕｏｒｏｐｈｅｎｙｌ］−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２０）Ｎ−（４−Ｆｌｕｏｒｏｐｈｅｎｙｌ）−Ｎ’−［２−ｆｌｕｏｒｏ−４−（｛２−［（ｐｙｒｒｏｌｉｄｉｎ−１−ｙｌｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）ｐｈｅｎｙｌ］ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２１）Ｎ−｛２−Ｆｌｕｏｒｏ−４−［（２−｛［（３−ｈｙｄｒｏｘｙａｚｅｔｉｄｉｎ−１−ｙｌ）ｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｄｉｎ−４−ｙｌ）ｏｘｙ］ｐｈｅｎｙｌ｝−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２２）Ｎ−［４−（｛２−［（１，３’−Ｂｉａｚｅｔｉｄｉｎ−１’−ｙｌｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）−２−ｆｌｕｏｒｏｐｈｅｎｙｌ］−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２３）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［３−（ｈｙｄｒｏｘｙｍｅｔｈｙｌ）ａｚｅｔｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２４）Ｎ−（４−｛［２−（｛［３−（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ａｚｅｔｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝−２−ｆｌｕｏｒｏｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２５）Ｎ−［４−（｛２−［（｛３−［（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ｍｅｔｈｙｌ］ａｚｅｔｉｄｉｎ−１−ｙｌ｝ｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）−２−ｆｌｕｏｒｏｐｈｅｎｙｌ］−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２６）Ｎ−｛２−Ｆｌｕｏｒｏ−４−［（２−｛［（４−ｈｙｄｒｏｘｙｐｉｐｅｒｉｄｉｎ−１−ｙｌ）ｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｄｉｎ−４−ｙｌ）ｏｘｙ］ｐｈｅｎｙｌ｝−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２７）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［４−（ｈｙｄｒｏｘｙｍｅｔｈｙｌ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２８）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［（３Ｒ）−３−ｈｙｄｒｏｘｙｐｙｒｒｏｌｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（２９）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［（３Ｓ）−３−ｈｙｄｒｏｘｙｐｙｒｒｏｌｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３０）Ｎ−［４−（｛２−［（Ａｚｅｔｉｄｉｎ−１−ｙｌｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）−２，５−ｄｉｆｌｕｏｒｏｐｈｅｎｙｌ］−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３１）Ｎ−｛２，５−Ｄｉｆｌｕｏｒｏ−４−［（２−｛［（３−ｈｙｄｒｏｘｙａｚｅｔｉｄｉｎ−１−ｙｌ）ｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｄｉｎ−４−ｙｌ）ｏｘｙ］ｐｈｅｎｙｌ｝−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３２）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［２−（｛［４−（４−ｍｅｔｈｙｌｐｉｐｅｒａｚｉｎ−１−ｙｌ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３３）Ｎ−［２，５−Ｄｉｆｌｕｏｒｏ−４−（｛２−［（｛３−［（ｄｉｍｅｔｈｙｌａｍｉｎｏ）ｍｅｔｈｙｌ］ａｚｅｔｉｄｉｎ−１−ｙｌ｝ｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）ｐｈｅｎｙｌ］−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３４）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［２−（｛［ｍｅｔｈｙｌ（１−ｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ−４−ｙｌ）ａｍｉｎｏ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３５）Ｎ−｛４−［（２−｛［３−（Ａｚｅｔｉｄｉｎ−１−ｙｌｍｅｔｈｙｌ）ａｚｅｔｉｄｉｎ−１−ｙｌｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｄｉｎ−４−ｙｌ）ｏｘｙ］−２，５−ｄｉｆｌｕｏｒｏｐｈｅｎｙｌ｝−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３６）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［２−（｛［３−（ｈｙｄｒｏｘｙｍｅｔｈｙｌ）ａｚｅｔｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３７）Ｎ−｛２，５−Ｄｉｆｌｕｏｒｏ−４−［（４−｛［（３−ｈｙｄｒｏｘｙａｚｅｔｉｄｉｎ−１−ｙｌ）ｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｍｉｄｉｎ−６−ｙｌ）ｏｘｙ］ｐｈｅｎｙｌ｝−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３８）Ｎ−［４−（｛４−［（｛３−［（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ｍｅｔｈｙｌ］ａｚｅｔｉｄｉｎ−１−ｙｌ｝ｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｍｉｄｉｎ−６−ｙｌ｝ｏｘｙ）−２，５−ｄｉｆｌｕｏｒｏｐｈｅｎｙｌ］−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（３９）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［４−（｛［３−（ｈｙｄｒｏｘｙｍｅｔｈｙｌ）ａｚｅｔｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｍｉｄｉｎ−６−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（４０）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［４−（｛［ｍｅｔｈｙｌ（１−ｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ−４−ｙｌ）ａｍｉｎｏ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｍｉｄｉｎ−６−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（４１）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［４−（｛［４−（４−ｍｅｔｈｙｌｐｉｐｅｒａｚｉｎ−１−ｙｌ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｍｉｄｉｎ−６−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（４２）Ｎ−（４−｛［２−（｛［４−（Ｄｉｍｅｔｈｙｌａｍｉｎｏ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝−２，５−ｄｉｆｌｕｏｒｏｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（４３）Ｎ−｛２，５−Ｄｉｆｌｕｏｒｏ−４−［（２−｛［（４−ｍｅｔｈｙｌｐｉｐｅｒａｚｉｎ−１−ｙｌ）ｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（４４）Ｎ−｛２，５−Ｄｉｆｌｕｏｒｏ−４−［（２−｛［（４−ｈｙｄｒｏｘｙｐｉｐｅｒｉｄｉｎ−１−ｙｌ）ｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｄｉｎ−４−ｙｌ）ｏｘｙ］ｐｈｅｎｙｌ｝−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（４５）Ｎ−｛４−［（２−｛［（４−Ａｚｅｔｉｄｉｎ−１−ｙｌｐｉｐｅｒｉｄｉｎ−１−ｙｌ）ｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｄｉｎ−４−ｙｌ）ｏｘｙ］ｏｘｙ｝−２，５−ｄｉｆｌｕｏｒｏｐｈｅｎｙｌ｝−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（４６）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［２−（｛［３−（２−ｄｉｍｅｔｈｙｌａｍｉｎｏａｃｅｔｏｘｙ）ａｚｅｔｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ、
（４７）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［２−（｛［（３Ｓ）−３−ｈｙｄｒｏｘｙｐｙｒｒｏｌｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅまたは
（４８）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［２−（｛［（３Ｒ）−３−ｈｙｄｒｏｘｙｐｙｒｒｏｌｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅである［１］記載の食道癌治療用組成物。
［２１］ 一般式（Ｉ）で表される化合物が、
（１）Ｎ−（２−Ｆｌｕｏｒｏ−４−｛［２−（｛［４−（４−ｍｅｔｈｙｌｐｉｐｅｒａｚｉｎ−１−ｙｌ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ
（２）Ｎ−［４−（｛２−［（ａｚｅｔｉｄｉｎ−１−ｙｌｃａｒｂｏｎｙｌ）ａｍｉｎｏ］ｐｙｒｉｄｉｎ−４−ｙｌ｝ｏｘｙ）−２−ｆｌｕｏｒｏｐｈｅｎｙｌ］−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ
（３）Ｎ−｛２，５−Ｄｉｆｌｕｏｒｏ−４−［（２−｛［（３−ｈｙｄｒｏｘｙａｚｅｔｉｄｉｎ−１−ｙｌ）ｃａｒｂｏｎｙｌ］ａｍｉｎｏ｝ｐｙｒｉｄｉｎ−４−ｙｌ）ｏｘｙ］ｐｈｅｎｙｌ｝−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ
（４）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［２−（｛［４−（４−ｍｅｔｈｙｌｐｉｐｅｒａｚｉｎ−１−ｙｌ）ｐｉｐｅｒｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ
（５）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［２−（｛［ｍｅｔｈｙｌ（１−ｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ−４−ｙｌ）ａｍｉｎｏ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅ
（６）Ｎ−（２，５−Ｄｉｆｌｕｏｒｏ−４−｛［２−（｛［３−（ｈｙｄｒｏｘｙｍｅｔｈｙｌ）ａｚｅｔｉｄｉｎ−１−ｙｌ］ｃａｒｂｏｎｙｌ｝ａｍｉｎｏ）ｐｙｒｉｄｉｎ−４−ｙｌ］ｏｘｙ｝ｐｈｅｎｙｌ）−Ｎ’−（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃｙｃｌｏｐｒｏｐａｎｅ−１，１−ｄｉｃａｒｂｏｘａｍｉｄｅである［１］記載の食道癌治療用組成物。
［２２］ 食道癌の患者に［１］〜［２１］のいずれか１記載の食道癌治療用組成物を投与することを特徴とする食道癌の治療方法。
［２３］ 食道癌治療用組成物を製造するための、上記一般式（Ｉ）で表される化合物もしくはその塩またはそれらの水和物の使用。
［２４］ 食道癌治療用組成物に使用するための、上記一般式（Ｉ）で表される化合物もしくはその塩またはそれらの水和物。   That is, the present invention provides the following [1] to [20].
[1] General formula

  (Wherein R¹Is a 3- to 10-membered non-aromatic heterocyclic group (provided that a nitrogen atom is necessarily contained in the atoms constituting the ring and a bond is drawn from the nitrogen atom) or a formula —NR^11aR^11b(Wherein R^11aAnd R^11bAre the same or different and are a hydrogen atom, C_1-6Alkyl group, C_3-6Alkenyl group, C_3-6Alkynyl group, C_3-10A cycloalkyl group, C_6-10An aryl group means a 5- to 10-membered heteroaryl group or a 4- to 10-membered non-aromatic heterocyclic group. However, R^11aAnd R^11bMay have a substituent selected from the following substituent group a or the following substituent group b.
[Substituent group a]
A halogen atom, a hydroxyl group, a mercapto group, a nitro group, a cyano group and an oxo group;
[Substituent group b]
C_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Alkynyl group, C_3-10A cycloalkyl group, C_6-10Aryl group, 5-10 membered heteroaryl group, 3-10 membered non-aromatic heterocyclic group, C_1-6Alkoxy group, C_3-6Alkenyloxy group, C_3-6Alkynyloxy group, C_3-10Cycloalkoxy group, C_6-10Aryloxy group, 5- to 10-membered heteroaryloxy group, 4- to 10-membered non-aromatic heterocyclic oxy group, C_1-6Alkylthio group, C_3-6Alkenylthio group, C_3-6Alkynylthio group, C_3-10A cycloalkylthio group, C_6-10Arylthio group, 5-10 membered heteroarylthio group, 4-10 membered non-aromatic heterocyclic thio group and formula -T¹-T²-T³
  (Where T¹Is a single bond or C_1-6An alkylene group is meant.
  T²Is a carbonyl group, a sulfinyl group, a sulfonyl group, a group represented by the formula —C (═O) —O—, a group represented by the formula —O—C (═O) —, or the formula —SO₂A group represented by -O-, a formula -O-SO₂A group represented by the formula: -NR^T1A group represented by the formula: -C (= O) -NR^T1A group represented by the formula: -NR^T1A group represented by -C (= O)-, the formula -SO₂-NR^T1A group represented by-or the formula -NR^T1-SO₂Means a group represented by-.
  T³Is a hydrogen atom, C_1-6Alkyl group, C_3-6Alkenyl group, C_3-6Alkynyl group, C_3-10A cycloalkyl group, C_6-10An aryl group means a 5-10 membered heteroaryl group or a 4-10 membered non-aromatic heterocyclic group.
  R^T1Is a hydrogen atom or C_1-6An alkyl group is meant. ), And each of the above groups may have a substituent selected from the following substituent group c.
[Substituent group c]
Halogen atom, hydroxyl group, mercapto group, nitro group, cyano group, oxo group, C_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Alkynyl group, C_3-10A cycloalkyl group, C_6-10Aryl group, 5-10 membered heteroaryl group, 3-10 membered non-aromatic heterocyclic group, C_1-6Alkoxy group, C_1-6Alkylthio group, mono-C_1-6Alkylamino and di-C_1-6An alkylamino group; ).
  However, R¹May have a substituent selected from the substituent group a or the substituent group b.
  R²And R³Means a hydrogen atom.
  R⁴, R⁵, R⁶And R⁷Are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a trifluoromethyl group, C_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Alkynyl group, C_1-6Alkoxy group, amino group, mono-C_1-6Alkylamino group, di-C_1-6Alkylamino group, formula -CO-R¹²(Wherein R¹²Is a hydrogen atom, a hydroxyl group, C_1-6Alkyl group, C_1-6Alkoxy group, amino group, mono-C_1-6An alkylamino group or di-C_1-6An alkylamino group is meant. ).
  R⁸Is a hydrogen atom or C_1-6An alkyl group is meant.
  R⁹Is a 3- to 10-membered non-aromatic heterocyclic group (provided that a nitrogen atom is necessarily contained in the atoms constituting the ring and a bond is drawn from the nitrogen atom) or a formula —NR^11aR^11b(Wherein R^11aAnd R^11bMeans a group represented by a group represented by the same meaning as defined above.
  However, R⁹May have a substituent selected from the substituent group a or the substituent group b.
  n means an integer of 1 to 2.
  X represents the formula -C (R¹⁰) = (Where R is¹⁰Is a hydrogen atom, a halogen atom, a cyano group, C_1-6Alkyl group, C_2-6Alkenyl group, C_2-6Alkynyl group, formula —CO—R¹²(Wherein R¹²Means the same as defined above. ). ) Or a nitrogen atom. )
A composition for treating esophageal cancer comprising a compound represented by the formula:
[2] R¹Is a 3- to 10-membered non-aromatic heterocyclic group (however, in the atoms constituting the ring, which may have a substituent selected from the substituent group a or the substituent group b described in [1] above) The composition for treating esophageal cancer according to [1], wherein a nitrogen atom is necessarily contained in and a bond is derived from the nitrogen atom).
[3] R¹May have a substituent selected from the substituent group a or the substituent group b described in [1] above

(Wherein, a represents an integer of 1 to 4) or a substituent selected from substituent group a or substituent group b described in [1] above. Good expression

(In the formula, b represents an integer of 1 to 3. Z represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfonyl group, or a formula —NR.^Z-(Wherein R^ZIs a hydrogen atom or C_1-6An alkyl group is meant. ). The composition for treating esophageal cancer according to [1], which is a group represented by:
[4] R¹Azetidin-1-yl group which may have a substituent selected from the following substituent group d, pyrrolidin-1-yl group which may have a substituent selected from the following substituent group d, A piperidin-1-yl group optionally having a substituent selected from the following substituent group d; an azepan-1-yl group optionally having a substituent selected from the following substituent group d; A piperazin-1-yl group optionally having a substituent selected from group d, a diazepan-1-yl group optionally having a substituent selected from substituent group d below, and the following substituent group a morpholin-4-yl group optionally having a substituent selected from d, a thiomorpholin-4-yl group optionally having a substituent selected from the following substituent group d, or the following substituent group d 1,1-dioxy optionally having a substituent selected from Thiomorpholine-4-yl group [1] for treating esophageal cancer composition.
[Substituent group d]
Halogen atom, hydroxyl group, mercapto group, cyano group, formyl group, oxo group, C_1-6Alkyl group, C_3-10A cycloalkyl group, C_1-6Alkoxy group, amino group, mono-C_1-6Alkylamino group, di-C_1-6Alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl and formula -T⁴-T⁵  (Where T⁴Means a carbonyl group or a sulfonyl group. T⁵Is C_1-6Alkyl group, C_3-10Cycloalkyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, hydroxyl group, C_1-6Alkoxy group, amino group, mono-C_1-6An alkylamino group or di-C_1-6An alkylamino group is meant. ), And each of the above groups is a hydroxyl group, C_1-6Alkyl group, di-C_1-6It may have an alkylamino group, an azetidinyl group or a pyrrolidinyl group.
[5] R¹An azetidin-1-yl group optionally having a substituent selected from the following substituent group e, a pyrrolidin-1-yl group optionally having a substituent selected from the following substituent group e, A piperidin-1-yl group optionally having a substituent selected from the following substituent group e; a piperazin-1-yl group optionally having a substituent selected from the following substituent group e; A diazepan-1-yl group which may have a substituent selected from group e, or a morpholin-4-yl group which may have a substituent selected from substituent group e below [1] The composition for esophageal cancer treatment as described.
[Substituent group e]
It consists of a methyl group, an ethyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group and a piperazinyl group, each of the above groups having a hydroxyl group, a methyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group or a piperidinyl group. May be.
[6] R¹Is an azetidin-1-yl group optionally having a substituent selected from the following substituent group g, a pyrrolidin-1-yl group having a substituent selected from the following substituent group g, and the following substituent group g The composition for esophageal cancer treatment according to [1], which is a piperidin-1-yl group having a substituent selected from: or a piperazin-1-yl group having a substituent selected from the following substituent group g:
[Substituent group g]
Dimethylamino group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, dimethylaminomethyl group, dimethylaminoethyl group, azetidin-1-ylmethyl group, pyrrolidin-1-ylmethyl group and piperidin-1-ylmethyl group, Each group may have a methyl group or a dimethylamino group.
[6-1] R¹An azetidin-1-yl group optionally having a substituent selected from the following substituent group g-1, a pyrrolidin-1-yl group having a substituent selected from the following substituent group g-1, Esophageal cancer treatment according to [1], which is a piperidin-1-yl group having a substituent selected from the substituent group g-1 or a piperazin-1-yl group having a substituent selected from the following substituent group g-1. Composition.
[Substituent group g-1]
Azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, dimethylaminomethyl group, dimethylaminoethyl group, azetidin-1-ylmethyl group, pyrrolidin-1-ylmethyl group and piperidin-1-ylmethyl group, It may have a methyl group or a dimethylamino group.
[6-2] R¹The composition for treating esophageal cancer according to [1], wherein is an azetidin-1-yl group having a dimethylamino group, a pyrrolidin-1-yl group having a dimethylamino group, or a piperidin-1-yl group having a dimethylamino group .
[6-3] R¹Is an azetidin-1-yl group optionally having a substituent selected from the following substituent group g-2, a pyrrolidin-1-yl group having a substituent selected from the following substituent group g-2, or The composition for esophageal cancer treatment according to [1], which is a piperidin-1-yl group having a substituent selected from substituent group g-2.
[Substituent group g-2]
Hydroxyl group, methoxy group, hydroxymethyl group and dimethylaminoacetoxy group.
[6-4] R¹[2- (dimethylamino) ethyl] piperazin-1-yl group, 4-pyrrolidin-1-ylpiperidin-1-yl group, 4-[(dimethylamino) methyl] piperidin-1-yl group, 4- Azetidin-1-ylpiperidin-1-yl group, 4- [3- (dimethylamino) azetidin-1-yl] piperidin-1-yl group, 4- (4-methylpiperazin-1-yl) piperidin-1- Yl group, 4- (1-methylpiperidin-4-yl) piperazin-1-yl group, 4- (1-methylazetidin-3-yl) piperazin-1-yl group, 4- (dimethylamino) piperidine- 1-yl group, 4- (azetidin-1-ylmethyl) piperidin-1-yl group, 4- (pyrrolidin-1-ylmethyl) piperidin-1-yl group, (3S) -3- (dimethylamino) Loridin-1-yl group, (3R) -3- (dimethylamino) pyrrolidin-1-yl group, azetidin-1-yl group, pyrrolidin-1-yl group, morpholin-4-yl group, 4-methylpiperazine- 1-yl group, 3-hydroxyazetidin-1-yl group, 1,3′-biazetidin-1′-yl group, 3- (hydroxymethyl) azetidin-1-yl group, 3- (dimethylamino) azetidine- 1-yl group, 3-[(dimethylamino) methyl] azetidin-1-yl group, 4-hydroxypiperidin-1-yl group, 4- (hydroxymethyl) piperidin-1-yl group, (3R) -3- Hydroxypyrrolidin-1-yl group, (3S) -3-hydroxypyrrolidin-1-yl group, 3- (azetidin-1-ylmethyl) azetidin-1-yl group or 3- (2- Methylamino acetoxy) azetidin-1-yl is based on [1] for treating esophageal cancer composition.
[7] R¹Is the formula -NR^11aR^11b(Wherein R^11aAnd R^11bIs R according to [1] above.^11aAnd R^11bMeans the same. The composition for treating esophageal cancer according to [1], which is a group represented by:
[8] R¹Is the formula -NR^11cR^11d(Wherein R^11cIs a hydrogen atom or C_1-6An alkyl group is meant. R^11dIs C_1-6Alkyl group or formula

(Wherein c represents an integer of 1 to 3. Z¹Is an oxygen atom, a sulfur atom, a carbonyl group, a sulfonyl group or a formula —NR^Z1-(Wherein R^Z1Is a hydrogen atom or C_1-6An alkyl group is meant. ). ). However, R^11dMay have a substituent selected from the substituent group a or substituent group b described in [1] above. The composition for treating esophageal cancer according to [1], which is a group represented by:
[9] R¹Is the formula -NR^11eR^11f(Wherein R^11eIs a hydrogen atom or C_1-6An alkyl group is meant. R^11fIs C_1-6It means an alkyl group, pyrrolidin-3-yl group, piperidin-3-yl group, piperidin-4-yl group or tetrahydropyran-4-yl group. However, R^11fMay have a substituent selected from the substituent group d described in [4] above. The composition for treating esophageal cancer according to [1], which is a group represented by:
[10] R¹Is the formula -NR^11gR^11h(Wherein R^11gMeans a hydrogen atom or a methyl group. R^11hMeans an n-propyl group, n-butyl group, pyrrolidin-3-yl group, piperidin-3-yl group, piperidin-4-yl group or tetrahydropyran-4-yl group. However, R^11hMay have a substituent selected from the following substituent group f. The composition for treating esophageal cancer according to [1], which is a group represented by:
[Substituent group f]
It consists of a methyl group, an ethyl group, an n-propyl group, an acetyl group, a dimethylamino group, a diethylamino group, an azetidinyl group, a pyrrolidinyl group, and a piperazinyl group, and each of the above groups may have a methyl group or a dimethylamino group. .
[11] R¹Is of the formula -N (CH₃) R¹¹ⁱ(Wherein R¹¹ⁱMeans an n-propyl group, an n-butyl group, a pyrrolidin-3-yl group or a piperidin-4-yl group. However, R¹¹ⁱHas a substituent selected from the following substituent group h. The composition for treating esophageal cancer according to [1], which is a group represented by:
[Substituent group h]
A dimethylamino group, a diethylamino group, a dimethylaminoethyl group, a dimethylaminopropyl group and a 1-methylazetidin-3-yl group;
[12] R¹Is of the formula -N (CH₃) R^11j(Wherein R^11jMeans 1-methylpiperidin-4-yl group or 1-ethylpiperidin-4-yl group. The composition for treating esophageal cancer according to [1], which is a group represented by:
[12-1] R¹Is of the formula -N (CH₃) R^11k(Wherein R^11kMeans a 3- (dimethylamino) propyl group or a 1- [2- (dimethylamino) ethyl] piperidin-4-yl group. The composition for treating esophageal cancer according to [1], which is a group represented by:
[12-2] R¹Are methyl (1-methylpiperidin-4-yl) amino group, (1-ethylpiperidin-4-yl) (methyl) amino group, [3- (dimethylamino) propyl] (methyl) amino group or {1- The composition for esophageal cancer treatment according to [1], which is a [2- (dimethylamino) ethyl] piperidin-4-yl} (methyl) amino group.
[13] R⁴, R⁵, R⁶And R⁷Are the same or different and each represents a hydrogen atom, a halogen atom or C_1-6The composition for esophageal cancer treatment according to any one of [1] to [12-2], which is an alkyl group.
[14] R⁸The composition for treating esophageal cancer according to any one of [1] to [13], wherein is a hydrogen atom.
[15] X is represented by the formula -C (R^10a) = (Where R is^10aMeans a hydrogen atom, a halogen atom or a cyano group. The composition for esophageal cancer treatment according to any one of [1] to [14], which is a group represented by:
[16] The composition for treating esophageal cancer according to any one of [1] to [14], wherein X is a nitrogen atom.
[17] The composition for treating esophageal cancer according to any one of [1] to [16], wherein n is 1.
[18] R⁹Which may have a substituent selected from the substituent group a or the substituent group b described in [1] above_1-6Mono-C which may have an alkylamino group and a substituent selected from the substituent group a or the substituent group b described in [1] above_3-10Mono-C which may have a cycloalkylamino group and a substituent selected from substituent group a or substituent group b described in [1] above_6-10An arylamino group, a mono-5 to 10-membered heteroarylamino group which may have a substituent selected from the substituent group a or the substituent group b described in [1] above, or the above [1] Any one of [1] to [17], which is a mono-4 to 10-membered non-aromatic heterocyclic amino group optionally having a substituent selected from substituent group a or substituent group b A composition for treating esophageal cancer.
[19] R⁹Which may have a substituent selected from the substituent group a or the substituent group b described in [1] above_3-10Mono-C which may have a cycloalkylamino group or a substituent selected from substituent group a or substituent group b described in [1] above_6-10The composition for treating esophageal cancer according to any one of [1] to [17], which is an arylamino group.
[19-1] R⁹Which may have a substituent selected from the following substituent group i_3-10Mono-C which may have a cycloalkylamino group or a substituent selected from the following substituent group i_6-10The composition for esophageal cancer treatment according to any one of [1] to [17], which is an arylamino group.
[Substituent group i]
Halogen atom, trifluoromethyl group, cyano group, C_1-6Alkyl groups and C_1-6An alkoxy group;
[19-2] R⁹A cyclopentylamino group which may have a substituent selected from the substituent group i described in [19-1] above, and a substituent selected from the substituent group i described in [19-1] above. A cyclohexylamino group which may have, a cycloheptylamino group which may have a substituent selected from the substituent group i described in [19-1] above, or the substitution described in [19-1] above. The composition for treating esophageal cancer according to any one of [1] to [17], which is a phenylamino group which may have a substituent selected from group i.
[20] The compound represented by the general formula (I) is:
(1) N- [4-({2-[({4- [2- (Dimethylamino) ethyl] piperazin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N '-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide,
(2) N- (2-Fluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(3) N- (4-Fluorophenyl) -N ′-{2-fluoro-4-[(2-{[(4-pyrrolidin-1-ylpiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} cyclopropane-1,1-dicboxamide,
(4) N- [4-({2-[({4-[(Dimethylamino) methyl] piperidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2-fluorphenyl] -N'- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(5) N- {4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] -2-fluorophenyl} -N ′-(4 -Fluorphenyl) cyclopropane-1, 1-dicboxamide,
(6) N- [4-({2-[({4- [3- (Dimethylamino) azetinin-1-yl] piperidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2- fluorphenyl] -N ′-(4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(7) N- (2-Fluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(8) N- (2-Fluoro-4-{[2-({[4- (1-methylpiperidin-4-yl) piperazin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(9) N- (2-Fluoro-4-{[2-({[4- (1-methylazetidin-3-yl) piperazin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(10) N- (4-{[2-({[4- (Dimethylamino) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(11) N- (4-{[2-({[4- (Azetidin-1-ylmethyl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(12) N- (4-Fluorophenyl) -N ′-(2-fluoro-4-{[2-({[4- (pyrrolidin-1-ylmethyl) piperidin-1-yl] carbonyl} amino) pyridin-4 -Yl] oxy} phenyl) cyclopropane-1,1-dicboxamide,
(13) N- (4-{[2-({[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(14) N- (4-{[2-({[(3R) -3- (Dimethylamino) pyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(15) N- (2-Fluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'-phenylcyclopropane -1,1-dicarboxamide,
(16) N- (2-Fluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'-phenylcyclopropane-1,1-dicboxamide,
(17) N- [4-({2-[({4- [3- (Dimethylamino) azetinin-1-yl] piperidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2- fluorphenyl] -N′-phenylcyclopropane-1,1-dicboxamide,
(18) N- (4-{[2-({[(1-Ethylpiperidin-4-yl) (methyl) amino] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N'- phenylcyclopropane-1,1-dicboxamide,
(19) N- [4-({2-[(Azetidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N ′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide,
(20) N- (4-Fluorophenyl) -N ′-[2-fluoro-4-({2-[(pyrrolidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) phenyl] cyclopropane-1,1 -Dicarboxamide,
(21) N- {2-Fluoro-4-[(2-{[(3-hydroxyzetin-1-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(22) N- [4-({2-[(1,3′-Biacetidin-1′-ylcarbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N ′-(4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(23) N- (2-Fluoro-4-{[2-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4 -Fluorphenyl) cyclopropane-1, 1-dicboxamide,
(24) N- (4-{[2-({[3- (Dimethylamino) azetinin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(25) N- [4-({2-[({3-[(Dimethylamino) methyl] azetinin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N′- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(26) N- {2-Fluoro-4-[(2-{[(4-hydroxypiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(27) N- (2-Fluoro-4-{[2-({[4- (hydroxymethyl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4 -Fluorphenyl) cyclopropane-1, 1-dicboxamide,
(28) N- (2-Fluoro-4-{[2-({[(3R) -3-hydroxypyrrolin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(29) N- (2-Fluoro-4-{[2-({[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(30) N- [4-({2-[(Azetidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) -2,5-difluorophenyl] -N ′-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide,
(31) N- {2,5-Difluoro-4--4-[(2-{[(3-hydroxyzetidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(32) N- (2,5-Difluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(33) N- [2,5-Difluoro-4-({2-[({3-[(dimethylamino) methyl] azetinin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) phenyl]- N ′-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(34) N- (2,5-Difluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(35) N- {4-[(2-{[3- (Azetidin-1-ylmethyl) azetinin-1-ylcarbonyl] amino} pyridin-4-yl) oxy] -2,5-difluorophenyl} -N′- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(36) N- (2,5-Difluoro-4-{[2-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N′- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(37) N- {2,5-Difluoro-4--4-[(4-{[(3-hydroxyzetidin-1-yl) carbonyl] amino} pyrimidin-6-yl) oxy] phenyl} -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(38) N- [4-({4-[({3-[(Dimethylamino) methyl] azetinin-1-yl} carbonyl) amino] pyrimidin-6-yl} oxy) -2,5-difluorophenyl] -N '-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide,
(39) N- (2,5-Difluoro-4-{[4-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyrimidin-6-yl] oxy} phenyl) -N'- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(40) N- (2,5-Difluoro-4-{[4-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyrimidin-6-yl] oxy} phenyl) -N ' -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(41) N- (2,5-Difluoro-4-{[4-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyrimidin-6-yl] oxy} phenyl) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(42) N- (4-{[2-({[4- (Dimethylamino) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2,5-difluorophenyl) -N '-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(43) N- {2,5-Difluoro-4--4-[(2-{[(4-methylpiperazin-1-yl) carbonyl] amino} pyridin-4-yl] oxy} phenyl) -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(44) N- {2,5-Difluoro-4-[(2-{[(4-hydroxypiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(45) N- {4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] oxy} -2,5-difluorophenyl} -N '-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide,
(46) N- (2,5-Difluoro-4-{[2-({[3- (2-dimethylaminoacetoxy) azetin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide,
(47) N- (2,5-Difluoro-4-{[2-({[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide or
(48) N- (2,5-Difluoro-4-{[2-({[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′ The composition for esophageal cancer treatment according to [1], which is-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide.
[21] The compound represented by the general formula (I) is:
(1) N- (2-Fluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide
(2) N- [4-({2-[(azetidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N ′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide
(3) N- {2,5-Difluoro-4-[(2-{[(3-hydroxyzetidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′-(4- fluorphenyl) cyclopropane-1,1-dicboxamide
(4) N- (2,5-Difluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicboxamide
(5) N- (2,5-Difluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide
(6) N- (2,5-Difluoro-4-{[2-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'- The composition for esophageal cancer treatment according to [1], which is (4-fluorophenyl) cyclopropane-1, 1-dicboxamide.
[22] A method for treating esophageal cancer, comprising administering the composition for treating esophageal cancer according to any one of [1] to [21] to a patient with esophageal cancer.
[23] Use of the compound represented by the above general formula (I) or a salt thereof or a hydrate thereof for producing a composition for treating esophageal cancer.
[24] A compound represented by the above general formula (I) or a salt thereof or a hydrate thereof for use in a composition for treating esophageal cancer.

  As disclosed in WO 2007/023768, the compound according to the present invention has an HGFR tyrosine kinase inhibitory action and inhibits the growth of human cancer cells based on HGFR activation. In addition, the compound according to the present invention inhibits migration of human cancer cells. Furthermore, the compounds according to the invention inhibit the proliferation of vascular endothelial cells via the HGF-HGFR signal.

  The compound according to the present invention inhibits the growth of human esophageal cancer cells (Pharmacological Test Example 1). Therefore, the compound according to the present invention is useful as a composition for treating esophageal cancer.

  However, the cancer type that is the target of the cancer therapeutic composition or cancer therapeutic agent is not particularly limited, and examples thereof include brain tumors (including pituitary adenoma and glioma), head and neck cancer, cervical cancer, jaw cancer, and maxilla. Cancer, submandibular gland cancer, oral cancer (including tongue cancer, oral floor cancer, gingival cancer, buccal mucosa cancer, hard palate cancer), salivary gland cancer, sublingual gland cancer, parotid gland cancer, nasal cavity cancer, sinus cancer (Including maxillary sinus cancer, frontal sinus cancer, ethmoid sinus cancer, sphenoid sinus cancer), laryngeal cancer (including supraglottic cancer, glottic cancer, subglottic cancer), esophageal cancer, lung cancer (primary bronchial cancer, non-bronchial cancer) Small cell lung cancer (including lung adenocarcinoma, squamous cell carcinoma, large cell lung cancer), small cell lung cancer (including buckwheat cell type (lymphocyte-like type), intermediate cell type), mixed small cell / large cell lung cancer) Breast cancer, pancreatic cancer (including pancreatic duct cancer), gastric cancer (including Skills gastric cancer, undifferentiated gastric cancer), biliary tract cancer (including bile duct cancer, gallbladder cancer), small intestine or duodenal cancer, large Cancer (including colon cancer, rectal cancer, cecal cancer, sigmoid colon cancer, ascending colon cancer, transverse colon cancer, descending colon cancer), bladder cancer, renal cancer (including renal cell carcinoma), liver cancer (hepatocellular carcinoma, Intrahepatic bile duct cancer), prostate cancer, uterine cancer (including cervical cancer, endometrial cancer), ovarian cancer, thyroid cancer, pharyngeal cancer (including nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), sarcoma (Eg, osteosarcoma, chondrosarcoma, Kaposi's sarcoma, myoma, hemangiosarcoma, fibrosarcoma, etc.), malignant lymphoma (including Hodgkin-type lymphoma, non-Hodgkin-type lymphoma), leukemia (eg, chronic myelogenous leukemia (CML), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL), lymphoma, multiple myeloma (MM), myelodysplastic syndrome, etc.), skin cancer (basal cell carcinoma, Squamous cell carcinoma, malignant melanoma, mycosis fungoides, Sezary Syndrome, actinic keratosis, Bowen's disease, including bar jet disease) and the like can be given melanoma.

  Hereinafter, the present invention will be described in detail with reference to definitions of symbols, terms and the like described in the present specification.

  In the present specification, the structural formula of a compound may represent a certain isomer for convenience, but the present invention includes all geometric isomers, optical isomers based on asymmetric carbon, and stereoisomerism that occur in the structure of the compound. Isomers such as isomers and tautomers, and mixtures of isomers, and are not limited to the description of the formula for convenience, and may be either isomer or mixture. Therefore, the compound of the present invention may have an asymmetric carbon atom in the molecule, and an optically active substance and a racemate may exist. However, the present invention is not limited to one and includes both. In addition, there is a case where a crystal polymorph may exist, but it is not limited in the same manner, and any one of the crystal forms may be a single crystal form or a mixture of crystal forms. The compounds according to the present invention include anhydrides and hydrates.

  In addition, a compound (so-called metabolite) produced by metabolism, such as oxidation, reduction, hydrolysis, and conjugation, in vivo, and a compound according to the present invention undergoes metabolism such as oxidation, reduction, hydrolysis, and conjugation in vivo. The compounds that produce the compounds according to the present invention (so-called prodrugs) are also encompassed by the claims of the present invention.

  The “salt” includes, for example, a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, a salt with an organic base, a salt with an acidic or basic amino acid, etc., among which pharmacologically acceptable. The salts to be prepared are preferred.

  Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include, for example, acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid. And salt.

  Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include salts with diethylamine, diethanolamine, meglumine, N, N-dibenzylethylenediamine and the like.

  Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The “C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, a 1-propyl group (n -Propyl group), 2-propyl group (i-propyl group), 2-methyl-1-propyl group (i-butyl group), 2-methyl-2-propyl group (t-butyl group), 1-butyl group (N-butyl group), 2-butyl group (s-butyl group), 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl-1-butyl group, 3-methyl-1-butyl group 2-methyl-2-butyl group, 3-methyl-2-butyl group, 2,2-dimethyl-1-propyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2- Methyl-1-pentyl group, 3-methyl-1-pentyl group, 4-methyl-1-pentyl group, 2-methyl Tyl-2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 2-methyl-3-pentyl group, 3-methyl-3-pentyl group, 2,3-dimethyl-1 -Butyl group, 3,3-dimethyl-1-butyl group, 2,2-dimethyl-1-butyl group, 2-ethyl-1-butyl group, 3,3-dimethyl-2-butyl group, 2,3- Examples thereof include a dimethyl-2-butyl group.

The “C _2-6 alkenyl group” means a straight or branched alkenyl group having 2 to 6 carbon atoms having one double bond. As a specific example, an ethenyl group (vinyl Group), 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, pentenyl group, hexenyl group and the like.

The “C _3-6 alkenyl group” means a straight or branched alkenyl group having 3 to 6 carbon atoms having one double bond, and specific examples include a 2-propenyl group. (Allyl group), 2-butenyl group, 3-butenyl group, pentenyl group, hexenyl group and the like.

The “C _2-6 alkynyl group” means a linear or branched alkynyl group having 1 to 3 carbon atoms and having one triple bond. Specific examples thereof include an ethynyl group, 1- Examples include propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group, hexynyl group and the like.

The “C _3-6 alkynyl group” means a straight or branched alkynyl group having 3 to 6 carbon atoms having one triple bond, and specific examples thereof include a 2-propynyl group, Examples include 2-butynyl group, 3-butynyl group, pentynyl group, hexynyl group and the like.

The “C _1-6 alkylene group” means a divalent group derived by removing any one hydrogen atom from the above-defined “C _1-6 alkyl group”, and specific examples include a methylene group. 1,2-ethylene group, 1,1-ethylene group, 1,3-propylene group, tetramethylene group, pentamethylene group, hexamethylene group and the like.

The “C _3-10 cycloalkyl group” means a monocyclic or bicyclic saturated aliphatic hydrocarbon group having 3 to 10 carbon atoms. Specific examples thereof include a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group. Cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, bicyclo [2.1.0] pentyl group, bicyclo [3.1.0] hexyl group, bicyclo [2.1.1] hexyl group , Bicyclo [4.1.0] heptyl group, bicyclo [2.2.1] heptyl group (norbornyl group), bicyclo [3.3.0] octyl group, bicyclo [3.2.1] octyl group, bicyclo [2.2.2] octyl group, bicyclo [4.3.0] nonyl group, bicyclo [3.3.1] nonyl group, bicyclo [4.4.0] decyl group (decalyl group), bicyclo [3 3.2] Decyl group I can get lost.

The “C _6-10 aryl group” means an aromatic hydrocarbon cyclic group having 6 to 10 carbon atoms, and specific examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and an indenyl group. Group, azulenyl group, heptalenyl group and the like.

  “Hetero atom” means a nitrogen atom, an oxygen atom or a sulfur atom.

  The “5- to 10-membered heteroaryl group” is an aromatic cyclic group having 5 to 10 atoms constituting the ring and containing 1 to 5 heteroatoms in the atoms constituting the ring. Specific examples include furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, furazanyl, thiadiazolyl, oxadiazolyl Group, pyridyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, triazinyl group, purinyl group, pteridinyl group, quinolyl group, isoquinolyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinazolinyl group, phthalazinyl group, imidazopyridyl group, imidazothia group Zolyl group, imidazooxazoly Group, benzothiazolyl group, benzoxazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, indazolyl group, pyrrolopyridyl group, thienopyridyl group, furopyridyl group, benzothiadiazolyl group, benzooxadiazolyl group, pyridopyrimidinyl group, Examples thereof include a benzofuryl group, a benzothienyl group, and a thienofuryl group.

  Preferable examples of the “5- to 10-membered heteroaryl group” include furyl group, thienyl group, pyrrolyl group, imidazolyl group, thiazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, isothiazolyl group, pyridyl group, and pyrimidinyl group. be able to.

“3- to 10-membered non-aromatic heterocyclic group” means
(1) The number of atoms constituting the ring is 3 to 10,
(2) containing 1 to 2 heteroatoms in the atoms constituting the ring;
(3) The ring may contain 1 to 2 heavy bonds,
(4) The ring may contain 1 to 3 carbonyl groups, sulfinyl groups or sulfonyl groups.
(5) A non-aromatic cyclic group which is monocyclic or bicyclic, and when a nitrogen atom is contained in the atoms constituting the ring, a bond may be taken out from the nitrogen atom. Specific examples include aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, azepanyl group, azocanyl group, piperazinyl group, diazepanyl group, diazocanyl group, diazabicyclo [2.2.1] heptyl group, morpholinyl group, thiomorpholinyl group, 1 1,1-dioxothiomorpholinyl group, oxiranyl group, oxetanyl group, tetrahydrofuryl group, tetrahydropyranyl group, dioxanyl group, tetrahydrothienyl group, tetrahydrothiopyranyl group, oxazolidinyl group, thiazolidinyl group and the like.

  Preferable examples of “3 to 10-membered non-aromatic heterocyclic group” include aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, azepanyl group, piperazinyl group, diazepanyl group, morpholinyl group, thiomorpholinyl group, 1,1 -A dioxothiomorpholinyl group, a tetrahydrofuryl group, and a tetrahydropyranyl group can be mentioned.

"4-10 membered non-aromatic heterocyclic group"
(1) The number of atoms constituting the ring is 4 to 10,
(2) containing 1 to 2 heteroatoms in the atoms constituting the ring;
(3) The ring may contain 1 to 2 double bonds,
(4) The ring may contain 1 to 3 carbonyl groups, sulfinyl groups or sulfonyl groups.
(5) A non-aromatic cyclic group which is monocyclic or bicyclic, and when a nitrogen atom is contained in the atoms constituting the ring, a bond may be taken out from the nitrogen atom. Specific examples include azetidinyl group, pyrrolidinyl group, piperidinyl group, azepanyl group, azocanyl group, piperazinyl group, diazepanyl group, diazocanyl group, diazabicyclo [2.2.1] heptyl group, morpholinyl group, thiomorpholinyl group, 1,1- Examples thereof include a dioxothiomorpholinyl group, an oxetanyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a dioxanyl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, an oxazolidinyl group, and a thiazolidinyl group.

  Preferable examples of the “4- to 10-membered non-aromatic heterocyclic group” include azetidinyl group, pyrrolidinyl group, piperidinyl group, azepanyl group, piperazinyl group, diazepanyl group, morpholinyl group, thiomorpholinyl group, 1,1-dioxo Examples thereof include a thiomorpholinyl group, a tetrahydrofuryl group, and a tetrahydropyranyl group.

The “C _3-10 cycloalkyl C _1-6 alkyl group” is a group obtained by substituting any hydrogen atom in the above-defined “C _1-6 alkyl group” with the above-defined “C _3-10 cycloalkyl group”. Specific examples include cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, cyclooctylmethyl group, cyclononylmethyl group, cyclodecylmethyl group, bicyclo [2 2.1] heptylmethyl group (norbornylmethyl group), bicyclo [4.4.0] decylmethyl group (decalylmethyl group), and the like.

The “C _6-10 aryl C _1-6 alkyl group” means a group in which any hydrogen atom in the above-defined “C _1-6 alkyl group” is substituted with the above-defined “C _6-10 aryl group”. Specific examples thereof include benzyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, phenethyl group, 1-naphthylethyl group, 2-naphthylethyl group and the like.

The “5 to 10-membered heteroaryl C _1-6 alkyl group” is a group in which any hydrogen atom in the above-defined “C _1-6 alkyl group” is substituted with the above-defined “5 to 10-membered heteroaryl group”. Specific examples include furylmethyl, thienylmethyl, pyrrolylmethyl, imidazolylmethyl, triazolylmethyl, tetrazolylmethyl, thiazolylmethyl, pyrazolylmethyl, oxazolylmethyl, iso Oxazolylmethyl, isothiazolylmethyl, furazanylmethyl, thiadiazolylmethyl, oxadiazolylmethyl, pyridylmethyl, pyrazinylmethyl, pyridazinylmethyl, pyrimidinylmethyl, triazinylmethyl , Furylethyl group, thienylethyl group, pyrrolylethyl group, imidazolylethyl group, tria Rylethyl group, tetrazolylethyl group, thiazolylethyl group, pyrazolylethyl group, oxazolylethyl group, isoxazolylethyl group, isothiazolylethyl group, furazanylethyl group, thiadiazolylethyl group, oxadiazolylethyl group, Examples include pyridylethyl group, pyrazinylethyl group, pyridazinylethyl group, pyrimidinylethyl group, triazinylethyl group and the like.

Preferable examples of the “5- to 10-membered heteroaryl C _1-6 alkyl group” include furylmethyl group, thienylmethyl group, pyrrolylmethyl group, imidazolylmethyl group, thiazolylmethyl group, pyrazolylmethyl group, oxazolylmethyl group, iso Oxazolylmethyl, isothiazolylmethyl, pyridylmethyl, pyrimidinylmethyl, furylethyl, thienylethyl, pyrrolylethyl, imidazolylethyl, thiazolylethyl, pyrazolylethyl, oxazolylethyl, isoxa Examples thereof include a zolylethyl group, an isothiazolylethyl group, a pyridylethyl group, and a pyrimidinylethyl group.

“3- to 10-membered non-aromatic heterocyclic C _1-6 alkyl group” means any hydrogen atom in the above-defined “C _1-6 alkyl group” as defined in the above-mentioned “3- to 10-membered non-aromatic heterocyclic ring”. A group substituted by the formula group, and specific examples include aziridinylmethyl group, azetidinylmethyl group, pyrrolidinylmethyl group, piperidinylmethyl group, azepanylmethyl group, azocanylmethyl group, piperazinylmethyl Group, diazepanylmethyl group, diazocanylmethyl group, morpholinylmethyl group, thiomorpholinylmethyl group, 1,1-dioxothiomorpholinylmethyl group, oxiranylmethyl group, oxetanylmethyl group Tetrahydrofurylmethyl group, tetrahydropyranylmethyl group, dioxanylmethyl group, tetrahydrothienylmethyl group, tetrahydrothiopyranylmethyl group, oxa Lydinylmethyl group, thiazolidinylmethyl group, aziridinylethyl group, azetidinylethyl group, pyrrolidinylethyl group, piperidinylethyl group, azepanylethyl group, azocanylethyl group, piperazinylethyl group, diazepanyl Ethyl group, diazocanylethyl group, morpholinylethyl group, thiomorpholinylethyl group, 1,1-dioxothiomorpholinylethyl group, oxiranylethyl group, oxetanylethyl group, tetrahydrofurylethyl group, Examples thereof include a tetrahydropyranylethyl group, a dioxanylethyl group, a tetrahydrothienylethyl group, a tetrahydrothiopyranylethyl group, an oxazolidinylethyl group, and a thiazolidinylethyl group.

Preferable examples of “3 to 10-membered non-aromatic heterocyclic C _1-6 alkyl group” include azetidinylmethyl group, pyrrolidinylmethyl group, piperidinylmethyl group, azepanylmethyl group, piperazinylmethyl group , Diazepanylmethyl group, morpholinylmethyl group, thiomorpholinylmethyl group, tetrahydrofurylmethyl group, azetidinylethyl group, pyrrolidinylethyl group, piperidinylethyl group, azepanylethyl group, piperazinyl Examples thereof include an ethyl group, a diazepanylethyl group, a morpholinylethyl group, a thiomorpholinylethyl group, and a tetrahydrofurylethyl group.

The “C _1-6 alkoxy group” means a group in which an oxygen atom is bonded to the terminal of the above-defined “C _1-6 alkyl group”, and specifically includes a methoxy group, an ethoxy group, 1- Propoxy group (n-propoxy group), 2-propoxy group (i-propoxy group), 2-methyl-1-propoxy group (i-butoxy group), 2-methyl-2-propoxy group (t-butoxy group), 1-butoxy group (n-butoxy group), 2-butoxy group (s-butoxy group), 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group, 2-methyl-1-butoxy group, 3 -Methyl-1-butoxy group, 2-methyl-2-butoxy group, 3-methyl-2-butoxy group, 2,2-dimethyl-1-propoxy group, 1-hexyloxy group, 2-hexyloxy group, 3 -Hexyloxy 2-methyl-1-pentyloxy group, 3-methyl-1-pentyloxy group, 4-methyl-1-pentyloxy group, 2-methyl-2-pentyloxy group, 3-methyl-2-pentyloxy group 4-methyl-2-pentyloxy group, 2-methyl-3-pentyloxy group, 3-methyl-3-pentyloxy group, 2,3-dimethyl-1-butoxy group, 3,3-dimethyl-1- Examples include butoxy group, 2,2-dimethyl-1-butoxy group, 2-ethyl-1-butoxy group, 3,3-dimethyl-2-butoxy group, 2,3-dimethyl-2-butoxy group and the like.

The “C _1-6 alkylthio group” means a group in which a sulfur atom is bonded to the terminal of the above-defined “C _1-6 alkyl group”. Specific examples thereof include a methylthio group, an ethylthio group, 1- Propylthio group (n-propylthio group), 2-propylthio group (i-propylthio group), 2-methyl-1-propylthio group (i-butylthio group), 2-methyl-2-propylthio group (t-butylthio group), 1-butylthio group (n-butylthio group), 2-butylthio group (s-butylthio group), 1-pentylthio group, 2-pentylthio group, 3-pentylthio group, 2-methyl-1-butylthio group, 3-methyl- 1-butylthio group, 2-methyl-2-butylthio group, 3-methyl-2-butylthio group, 2,2-dimethyl-1-propylthio group, 1-hexylthio group, 2-hexyl group Ruthio group, 3-hexylthio group, 2-methyl-1-pentylthio group, 3-methyl-1-pentylthio group, 4-methyl-1-pentylthio group, 2-methyl-2-pentylthio group, 3-methyl-2 -Pentylthio group, 4-methyl-2-pentylthio group, 2-methyl-3-pentylthio group, 3-methyl-3-pentylthio group, 2,3-dimethyl-1-butylthio group, 3,3-dimethyl-1- Examples thereof include a butylthio group, a 2,2-dimethyl-1-butylthio group, a 2-ethyl-1-butylthio group, a 3,3-dimethyl-2-butylthio group, and a 2,3-dimethyl-2-butylthio group.

The “C _3-6 alkenyloxy group” means a group in which an oxygen atom is bonded to the terminal of the above-mentioned definition “C _3-6 alkenyl group”. Specifically, for example, a 2-propenyloxy group ( Allyloxy group), 2-butenyloxy group, 3-butenyloxy group, pentenyloxy group, hexenyloxy group and the like.

The “C _3-6 alkenylthio group” means a group in which a sulfur atom is bonded to the terminal of the above definition “C _3-6 alkenyl group”. As a specific example, as a specific example, 2- Examples include propenylthio group (allylthio group), 2-butenylthio group, 3-butenylthio group, pentenylthio group, hexenylthio group and the like.

The “C _3-6 alkynyloxy group” means a group in which an oxygen atom is bonded to the terminal of the above definition “C _3-6 alkynyl group”. Specific examples thereof include a 2-propynyloxy group, 2 -Butynyloxy group, 3-butynyloxy group, pentynyloxy group, hexynyloxy group and the like can be mentioned.

The “C _3-6 alkynylthio group” means a group in which a sulfur atom is bonded to the terminal of the above-defined “C _3-6 alkynyl group”. Specific examples thereof include 2-propynylthio group, 2 -Butynylthio group, 3-butynylthio group, pentynylthio group, hexynylthio group and the like can be mentioned.

The “C _3-10 cycloalkoxy group” means a group in which an oxygen atom is bonded to the terminal of the above-defined “C _3-10 cycloalkyl group”. Specific examples thereof include a cyclopropoxy group, cyclobutoxy group Group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy group and the like.

The “C _3-10 cycloalkylthio group” means a group in which a sulfur atom is bonded to the terminal of the above definition “C _3-10 cycloalkyl group”. Specific examples include a cyclopropylthio group, Examples thereof include a butylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group, and a cyclooctylthio group.

The “C _6-10 aryloxy group” means a group in which an oxygen atom is bonded to the terminal of the above-defined “C _6-10 aryl group”. Specific examples thereof include a phenoxy group and a 1-naphthoxy group. 2-naphthoxy group, indenyloxy group, azulenyloxy group, heptalenyloxy group and the like.

The “C _6-10 arylthio group” means a group in which a sulfur atom is bonded to the terminal of the above-defined “C _6-10 aryl group”. Specific examples include a phenylthio group, a 1-naphthylthio group, A 2-naphthylthio group, an indenylthio group, an azulenylthio group, a heptaenylthio group, and the like can be given.

  The “5 to 10-membered heteroaryloxy group” means a group in which an oxygen atom is bonded to the terminal of the above-mentioned definition “5 to 10-membered heteroaryl group”. Specific examples include a furyloxy group and thienyl. Oxy group, pyrrolyloxy group, imidazolyloxy group, triazolyloxy group, thiazolyloxy group, pyrazolyloxy group, oxazolyloxy group, isoxazolyloxy group, isothiazolyloxy group, furazanyloxy group, thiadiazolyloxy group, Examples thereof include an oxadiazolyloxy group, a pyridyloxy group, a pyrazinyloxy group, a pyridazinyloxy group, a pyrimidinyloxy group, and a triazinyloxy group.

  The “5 to 10-membered heteroarylthio group” means a group in which a sulfur atom is bonded to the terminal of the above-mentioned definition “5 to 10-membered heteroaryl group”. Specific examples include a furylthio group and a thienylthio group. , Pyrrolylthio group, imidazolylthio group, triazolylthio group, thiazolylthio group, pyrazolylthio group, oxazolylthio group, isoxazolylthio group, isothiazolylthio group, furazanylthio group, thiadiazolylthio group, oxadiazolylthio group, pyridylthio group , Pyrazinylthio group, pyridazinylthio group, pyrimidinylthio group, triazinylthio group and the like.

  “4- to 10-membered non-aromatic heterocyclic group” means a group in which an oxygen atom is bonded to the terminal of the above-mentioned definition “4- to 10-membered non-aromatic heterocyclic group”. Is an azetidinyloxy group, pyrrolidinyloxy group, piperidinyloxy group, azepanyloxy group, azocanyloxy group, piperazinyloxy group, diazepanyloxy group, diazocanyloxy group, morpholinyloxy group Thiomorpholinyloxy group, 1,1-dioxothiomorpholinyloxy group, oxetanyloxy group, tetrahydrofuryloxy group, tetrahydropyranyloxy group, tetrahydrothienyloxy group, tetrahydrothiopyranyloxy group, etc. It is done.

  “4- to 10-membered non-aromatic heterocyclic thio group” means a group in which a sulfur atom is bonded to the terminal of the above-mentioned definition “4- to 10-membered non-aromatic heterocyclic group”. Azetidinylthio group, pyrrolidinylthio group, piperidinylthio group, azepanylthio group, azocanylthio group, piperazinylthio group, diazepanylthio group, diazocanylthio group, oxetanylthio group, tetrahydrofurylthio group, tetrahydropyranylthio group, tetrahydrothienylthio group, tetrahydro And thiopyranylthio group.

“Mono-C _1-6 alkylamino group” means a group in which one hydrogen atom in an amino group is substituted with the above-defined “C _1-6 alkyl group”. Group, ethylamino group, 1-propylamino group (n-propylamino group), 2-propylamino group (i-propylamino group), 2-methyl-1-propylamino group (i-butylamino group), 2 -Methyl-2-propylamino group (t-butylamino group), 1-butylamino group (n-butylamino group), 2-butylamino group (s-butylamino group), 1-pentylamino group, 2- Pentylamino group, 3-pentylamino group, 2-methyl-1-butylamino group, 3-methyl-1-butylamino group, 2-methyl-2-butylamino group, 3-methyl-2-butylamino group, 2,2-dimension Ru-1-propylamino group, 1-hexylamino group, 2-hexylamino group, 3-hexylamino group, 2-methyl-1-pentylamino group, 3-methyl-1-pentylamino group, 4-methyl- 1-pentylamino group, 2-methyl-2-pentylamino group, 3-methyl-2-pentylamino group, 4-methyl-2-pentylamino group, 2-methyl-3-pentylamino group, 3-methyl- 3-pentylamino group, 2,3-dimethyl-1-butylamino group, 3,3-dimethyl-1-butylamino group, 2,2-dimethyl-1-butylamino group, 2-ethyl-1-butylamino Group, 3,3-dimethyl-2-butylamino group, 2,3-dimethyl-2-butylamino group and the like.

The “mono-C _3-10 cycloalkylamino group” means a group in which one hydrogen atom in an amino group is substituted with the above-defined “C _3-10 cycloalkyl group”. Examples thereof include a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, a cyclohexylamino group, a cycloheptylamino group, and a cyclooctylamino group.

“Mono-C _6-10 arylamino group” means a group in which one hydrogen atom in an amino group is substituted with the above-defined “C _6-10 aryl group”. Group, 1-naphthylamino group, 2-naphthylamino group, indenylamino group, azulenylamino group, heptalenylamino group and the like.

  “Mono-5 to 10-membered heteroarylamino group” means a group in which one hydrogen atom in an amino group is substituted with the above-mentioned “5 to 10-membered heteroaryl group”. , Furylamino group, thienylamino group, pyrrolylamino group, imidazolylamino group, triazolylamino group, tetrazolylamino group, thiazolylamino group, pyrazolylamino group, oxazolylamino group, isoxazolylamino group, isothiazo Examples include a tolylamino group, a furazanylamino group, a thiadiazolylamino group, an oxadiazolylamino group, a pyridylamino group, a pyrazinylamino group, a pyridazinylamino group, a pyrimidinylamino group, and a triazinylamino group.

  Preferable examples of the “mono-5 to 10-membered heteroarylamino group” include a furylamino group, a thienylamino group, a pyrrolylamino group, an imidazolylamino group, a thiazolylamino group, a pyrazolylamino group, an oxazolylamino group, and an isoxazolyl. Examples thereof include a ruamino group, an isothiazolylamino group, a pyridylamino group, and a pyrimidinylamino group.

  “Mono-4 to 10-membered non-aromatic heterocyclic amino group” means a group in which one hydrogen atom in the amino group is substituted with the above-mentioned definition “4 to 10-membered non-aromatic heterocyclic group”. Specific examples include azetidinylamino group, pyrrolidinylamino group, piperidinylamino group, azepanylamino group, azocanylamino group, piperazinylamino group, diazepanylamino group, diazocanylamino group, Morpholinylamino group, thiomorpholinylamino group, 1,1-dioxothiomorpholinylamino group, oxetanylamino group, tetrahydrofurylamino group, tetrahydropyranylamino group, tetrahydrothienylamino group, tetrahydrothiopyranyl An amino group etc. are mention | raise | lifted.

  Preferable examples of “mono-4 to 10-membered non-aromatic heterocyclic amino group” include pyrrolidinylamino group, piperidinylamino group, azepanylamino group, piperazinylamino group, diazepanylamino group, Examples thereof include a morpholinylamino group, a thiomorpholinylamino group, and a tetrahydrofurylamino group.

The "di -C _1-6 alkylamino group", the two hydrogen atoms in an amino group, each same or different, means a group obtained by substituting the above-defined "C _1-6 alkyl group", specifically Examples include N, N-dimethylamino group, N, N-diethylamino group, N, N-di-n-propylamino group, N, N-di-i-propylamino group, N, N-di-n. -Butylamino group, N, N-di-i-butylamino group, N, N-di-s-butylamino group, N, N-di-t-butylamino group, N-ethyl-N-methylamino group N-propyl-N-methylamino group, Ni-propyl-N-methylamino group, Nn-butyl-N-methylamino group, Ni-butyl-N-methylamino group, N -S-butyl-N-methylamino group, Nt-butyl-N-methylamino group And the like.

  Below, each substituent in the compound which concerns on this invention shown by the said general formula (I) is demonstrated.

（式中、ａは、１ないし４の整数を意味する。）で表される基、式

（式中、ｂは、１ないし３の整数を意味する。Ｚは、酸素原子、硫黄原子、カルボニル基、スルホニル基または式−ＮＲ^Ｚ−（式中、Ｒ^Ｚは、水素原子またはＣ_１−６アルキル基を意味する。）で表される基を意味する。）で表される基（ただし、上記式（ＩＩ）および式（ＩＩＩ）で表される基は、下記置換基群ａまたは下記置換基群ｂから選ばれる置換基を有していてもよい。）または式−ＮＲ^１１ｃＲ^１１ｄ（式中、Ｒ^１１ｃは、水素原子またはＣ_１−６アルキル基を意味する。Ｒ^１１ｄは、Ｃ_１−６アルキル基または式

（式中、ｃは、１ないし３の整数を意味する。Ｚ^１は、酸素原子、硫黄原子、カルボニル基、スルホニル基または式−ＮＲ^Ｚ１−（式中、Ｒ^Ｚ１は、水素原子またはＣ_１−６アルキル基を意味する。）で表される基を意味する。）で表される基を意味する。ただし、Ｒ^１１ｄは、下記置換基群ａまたは下記置換基群ｂから選ばれる置換基を有していてもよい。）で表される基があげられる。
Ｒ^１のより好適な例としては、アゼチジン−１−イル基、ピロリジン−１−イル基、ピペリジン−１−イル基、アゼパン−１−イル基、ピペラジン−１−イル基、ジアゼパン−１−イル基、モルホリン−４−イル基、チオモルホリン−４−イル基、１，１−ジオキソチオモルホリン−４−イル基または式−ＮＲ^１１ｅＲ^１１ｆ（式中、Ｒ^１１ｅは、水素原子またはＣ_１−６アルキル基を意味する。Ｒ^１１ｆは、Ｃ_１−６アルキル基、ピロリジン−３−イル基、ピペリジン−３−イル基、ピペリジン−４−イル基またはテトラヒドロピラン−４−イル基を意味する。ただし、Ｒ^１１ｆは、下記置換基群ｄから選ばれる置換基を有していてもよい。）で表される基（ただし、上記各基は、下記置換基群ｄから選ばれる置換基を有していてもよい。）があげられる。
Ｒ^１のさらに好適な例としては、アゼチジン−１−イル基、ピロリジン−１−イル基、ピペリジン−１−イル基、ピペラジン−１−イル基、ジアゼパン−１−イル基、モルホリン−４−イル基（ただし、上記各基は、下記置換基群ｅから選ばれる置換基を有していてもよい。）または式−ＮＲ^１１ｇＲ^１１ｈ（式中、Ｒ^１１ｇは、水素原子またはメチル基を意味する。Ｒ^１１ｈは、ｎ−プロピル基、ｎ−ブチル基、ピロリジン−３−イル基、ピペリジン−３−イル基、ピペリジン−４−イル基またはテトラヒドロピラン−４−イル基を意味する。ただし、Ｒ^１１ｈは、下記置換基群ｆから選ばれる置換基を有していてもよい。）で表される基があげられる。
Ｒ^１の特に好適な例としては、アゼチジン−１−イル基、ピロリジン−１−イル基、ピペリジン−１−イル基もしくはピペラジン−１−イル基（ただし、アゼチジン−１−イル基は、下記置換基群ｇから選ばれる置換基を有していてもよく、ピロリジン−１−イル基、ピペリジン−１−イル基およびピペラジン−１−イル基は、下記置換基群ｇから選ばれる置換基を有する。）または式−Ｎ（ＣＨ_３）Ｒ^１１ｉ（式中、Ｒ^１１ｉは、ｎ−プロピル基、ｎ−ブチル基、ピロリジン−３−イル基またはピペリジン−４−イル基を意味する。ただし、Ｒ^１１ｉは、下記置換基群ｈから選ばれる置換基を有する。）で表される基があげられる。
Ｒ^１の最も好適な例としては、アゼチジン−１−イル基、ピロリジン−１−イル基、ピペリジン−１−イル基またはピペラジン−１−イル基（ただし、アゼチジン−１−イル基は、下記置換基群ｇ−１から選ばれる置換基を有していてもよく、ピロリジン−１−イル基、ピペリジン−１−イル基およびピペラジン−１−イル基は、下記置換基群ｇ−１から選ばれる置換基を有する。）、ジメチルアミノ基を有するアゼチジン−１−イル基、ジメチルアミノ基を有するピロリジン−１−イル基、ジメチルアミノ基を有するピペリジン−１−イル基、式−Ｎ（ＣＨ_３）Ｒ^１１ｊ（式中、Ｒ^１１ｊは、１−メチルピペリジン−４−イル基または１−エチルピペリジン−４−イル基を意味する。）で表される基、下記置換基群ｇ−２から選ばれる置換基を有していてもよいアゼチジン−１−イル基、下記置換基群ｇ−２から選ばれる置換基を有するピロリジン−１−イル基、下記置換基群ｇ−２から選ばれる置換基を有するピペリジン−１−イル基または式−Ｎ（ＣＨ_３）Ｒ^１１ｋ（式中、Ｒ^１１ｋは、１−メチルピペリジン−４−イル基、１−エチルピペリジン−４−イル基、３−（ジメチルアミノ）プロピル基または１−［２−（ジメチルアミノ）エチル］ピペリジン−４−イル基を意味する。）で表される基があげられる。
また、Ｒ^１の最も好適な例としては、［２−（ジメチルアミノ）エチル］ピペラジン−１−イル基、４−ピロリジン−１−イルピペリジン−１−イル基、４−［（ジメチルアミノ）メチル］ピペリジン−１−イル基、４−アゼチジン−１−イルピペリジン−１−イル基、４−［３−（ジメチルアミノ）アゼチジン−１−イル］ピペリジン−１−イル基、４−（４−メチルピペラジン−１−イル）ピペリジン−１−イル基、４−（１−メチルピペリジン−４−イル）ピペラジン−１−イル基、４−（１−メチルアゼチジン−３−イル）ピペラジン−１−イル基、４−（ジメチルアミノ）ピペリジン−１−イル基、４−（アゼチジン−１−イルメチル）ピペリジン−１−イル基、４−（ピロリジン−１−イルメチル）ピペリジン−１−イル基、（３Ｓ）−３−（ジメチルアミノ）ピロリジン−１−イル基、（３Ｒ）−３−（ジメチルアミノ）ピロリジン−１−イル基、アゼチジン−１−イル基、ピロリジン−１−イル基、モルホリン−４−イル基、４−メチルピペラジン−１−イル基、３−ヒドロキシアゼチジン−１−イル基、１，３’−ビアゼチジン−１’−イル基、３−（ヒドロキシメチル）アゼチジン−１−イル基、３−（ジメチルアミノ）アゼチジン−１−イル基、３−［（ジメチルアミノ）メチル］アゼチジン−１−イル基、４−ヒドロキシピペリジン−１−イル基、４−（ヒドロキシメチル）ピペリジン−１−イル基、（３Ｒ）−３−ヒドロキシピロリジン−１−イル基、（３Ｓ）−３−ヒドロキシピロリジン−１−イル基、３−（アゼチジン−１−イルメチル）アゼチジン−１−イル基、３−（２−ジメチルアミノアセトキシ）アゼチジン−１−イル基、メチル（１−メチルピペリジン−４−イル）アミノ基、（１−エチルピペリジン−４−イル）（メチル）アミノ基、［３−（ジメチルアミノ）プロピル］（メチル）アミノ基または｛１−［２−（ジメチルアミノ）エチル］ピペリジン−４−イル｝（メチル）アミノ基があげられる。 [Significance of R ¹ ]
R ¹ is a 3- to 10-membered non-aromatic heterocyclic group (provided that a nitrogen atom is necessarily contained in the atoms constituting the ring and a bond is out of the nitrogen atom) or a formula- NR ^11a R ^11b (wherein R ^11a and R ^11b are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-10 cycloalkyl group) Group, C _6-10 aryl group, 5-10 membered heteroaryl group or 4-10 membered non-aromatic heterocyclic group, provided that R ^11a and R ^11b are the following substituent group a or the following substituents Which may have a substituent selected from group b).
However, R ¹ may have a substituent selected from the following substituent group a or the following substituent group b.
Suitable examples of R ¹ include the formula

(Wherein a represents an integer of 1 to 4), a group represented by the formula

(In the formula, b represents an integer of 1 to 3. Z represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfonyl group, or a formula —NR ^Z — (wherein R ^Z represents a hydrogen atom or C _{1- 6} represents a group represented by formula (II) and a formula (III) are represented by the following substituent group a or the following groups: Which may have a substituent selected from the substituent group b.) Or a formula —NR ^11c R ^11d (wherein R ^11c represents a hydrogen atom or a C _1-6 alkyl group. R ^11d represents C _1-6 alkyl group or formula

(Wherein c represents an integer of 1 to 3. Z ¹ represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfonyl group, or a formula —NR ^Z1 — (wherein R ^Z1 represents a hydrogen atom or C ₁ Means a _-6 alkyl group.) Means a group represented by). However, R ^11d may have a substituent selected from the following substituent group a or the following substituent group b. ).
More preferred examples of R ¹ include azetidin-1-yl group, pyrrolidin-1-yl group, piperidin-1-yl group, azepan-1-yl group, piperazin-1-yl group, diazepan-1-yl A group, morpholin-4-yl group, thiomorpholin-4-yl group, 1,1-dioxothiomorpholin-4-yl group or a formula -NR ^11e R ^11f (wherein R ^11e is a hydrogen atom or C ₁ ^{.R 11f} meaning _-6 alkyl group _means a _{C 1-6} alkyl group, pyrrolidin-3-yl group, piperidin-3-yl group, piperidin-4-yl group or tetrahydropyran-4-yl group However, R ^11f may have a substituent selected from the following substituent group d. (However, each of the above groups is a substituent selected from the following substituent group d.) Have Good).
More preferred examples of R ¹ include azetidin-1-yl group, pyrrolidin-1-yl group, piperidin-1-yl group, piperazin-1-yl group, diazepan-1-yl group, morpholin-4-yl A group (wherein each group may have a substituent selected from the following substituent group e) or a formula —NR ^11g R ^11h (wherein R ^11g represents a hydrogen atom or a methyl group) R ^11h represents an n-propyl group, an n-butyl group, a pyrrolidin-3-yl group, a piperidin-3-yl group, a piperidin-4-yl group, or a tetrahydropyran-4-yl group, provided that R ^11h may have a substituent selected from the following substituent group f.).
Particularly preferred examples of R ¹ include azetidin-1-yl group, pyrrolidin-1-yl group, piperidin-1-yl group or piperazin-1-yl group (wherein azetidin-1-yl group is substituted by The pyrrolidin-1-yl group, the piperidin-1-yl group, and the piperazin-1-yl group may have a substituent selected from the following substituent group g. ) Or the formula —N (CH ₃ ) R ¹¹ⁱ (wherein R ¹¹ⁱ represents an n-propyl group, an n-butyl group, a pyrrolidin-3-yl group, or a piperidin-4-yl group, provided that R ¹¹ⁱ has a substituent selected from the following substituent group h)).
Most preferred examples of R ¹ include azetidin-1-yl group, pyrrolidin-1-yl group, piperidin-1-yl group or piperazin-1-yl group (wherein azetidin-1-yl group is substituted by The pyrrolidin-1-yl group, the piperidin-1-yl group and the piperazin-1-yl group may be selected from the following substituent group g-1 which may have a substituent selected from the group g-1. Having a substituent.), An azetidin-1-yl group having a dimethylamino group, a pyrrolidin-1-yl group having a dimethylamino group, a piperidin-1-yl group having a dimethylamino group, a formula —N (CH ₃ ) R ^{11j (wherein, R 11j} is meant 1-methylpiperidin-4-yl group or 1-ethyl-piperidin-4-yl group.), a group represented by selected from the following substituent group g-2 An azetidin-1-yl group optionally having a substituent, a pyrrolidin-1-yl group having a substituent selected from the following substituent group g-2, and a substituent selected from the following substituent group g-2 A piperidin-1-yl group or a formula —N (CH ₃ ) R ^11k (wherein R ^11k is a 1-methylpiperidin-4-yl group, a 1-ethylpiperidin-4-yl group, 3- (dimethylamino) A propyl group or a 1- [2- (dimethylamino) ethyl] piperidin-4-yl group).
The most preferred examples of R ¹ include [2- (dimethylamino) ethyl] piperazin-1-yl group, 4-pyrrolidin-1-ylpiperidin-1-yl group, and 4-[(dimethylamino) methyl. ] Piperidin-1-yl group, 4-azetidin-1-yl piperidin-1-yl group, 4- [3- (dimethylamino) azetidin-1-yl] piperidin-1-yl group, 4- (4-methyl) Piperazin-1-yl) piperidin-1-yl group, 4- (1-methylpiperidin-4-yl) piperazin-1-yl group, 4- (1-methylazetidin-3-yl) piperazin-1-yl Group, 4- (dimethylamino) piperidin-1-yl group, 4- (azetidin-1-ylmethyl) piperidin-1-yl group, 4- (pyrrolidin-1-ylmethyl) piperidin-1-yl group, 3S) -3- (dimethylamino) pyrrolidin-1-yl group, (3R) -3- (dimethylamino) pyrrolidin-1-yl group, azetidin-1-yl group, pyrrolidin-1-yl group, morpholine-4 -Yl group, 4-methylpiperazin-1-yl group, 3-hydroxyazetidin-1-yl group, 1,3'-biazetidin-1'-yl group, 3- (hydroxymethyl) azetidin-1-yl group 3- (dimethylamino) azetidin-1-yl group, 3-[(dimethylamino) methyl] azetidin-1-yl group, 4-hydroxypiperidin-1-yl group, 4- (hydroxymethyl) piperidin-1- Yl group, (3R) -3-hydroxypyrrolidin-1-yl group, (3S) -3-hydroxypyrrolidin-1-yl group, 3- (azetidin-1-ylmethyl) azetidine 1-yl group, 3- (2-dimethylaminoacetoxy) azetidin-1-yl group, methyl (1-methylpiperidin-4-yl) amino group, (1-ethylpiperidin-4-yl) (methyl) amino group , [3- (dimethylamino) propyl] (methyl) amino group or {1- [2- (dimethylamino) ethyl] piperidin-4-yl} (methyl) amino group.

[Significance of Substituent Group a]
The substituent group a means a group consisting of a halogen atom, a hydroxyl group, a mercapto group, a nitro group, a cyano group, and an oxo group.

[Significance of Substituent Group b]
Substituent group b includes a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _6-10 aryl group, a 5-10 membered heteroaryl group, 3- to 10-membered non-aromatic heterocyclic group, C _1-6 alkoxy group, C _3-6 alkenyloxy group, C _3-6 alkynyloxy group, C _3-10 cycloalkoxy group, C _6-10 aryloxy group 5- to 10-membered heteroaryloxy group, 4- to 10-membered non-aromatic heterocyclic oxy group, C _1-6 alkylthio group, C _3-6 alkenylthio group, C _3-6 alkynylthio group, C _3-10 cyclo An alkylthio group, a C _6-10 arylthio group, a 5-10 membered heteroarylthio group, a 4-10 membered non-aromatic heterocyclic thio group, and a formula -T ¹ -T ² -T ³ (wherein T ¹ is a single bond or _{C 1-} It means an alkylene group.
T ² is a carbonyl group, a sulfinyl group, a sulfonyl group, a group represented by the formula —C (═O) —O—, a group represented by the formula —O—C (═O) —, or a formula —SO ₂ —. A group represented by the formula O—, a group represented by the formula —O—SO ₂ —, a group represented by the formula —NR ^T1 —, a group represented by the formula —C (═O) —NR ^T1 —, a formula It means a group represented by —NR ^T1 —C (═O) —, a group represented by the formula —SO ₂ —NR ^T1 — or a group represented by the formula —NR ^T1 —SO ₂ —.
T ³ is a hydrogen atom, a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-10 cycloalkyl group, a C _6-10 aryl group, or a 5-10 membered heteroaryl group. Or means a 4- to 10-membered non-aromatic heterocyclic group.
R ^T1 means a hydrogen atom or a C _1-6 alkyl group. ) Represents a group consisting of groups represented by
However, each group described in the substituent group b may have a substituent selected from the following substituent group c.

[Significance of Substituent Group c]
Substituent group c includes a halogen atom, a hydroxyl group, a mercapto group, a nitro group, a cyano group, an oxo group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, and a C _3-10 cycloalkyl group. Group, C _6-10 aryl group, 5-10 membered heteroaryl group, 3-10 membered non-aromatic heterocyclic group, C _1-6 alkoxy group, C _1-6 alkylthio group, mono-C _1-6 alkyl It means a group consisting of an amino group and a di-C _1-6 alkylamino group.

[Significance of Substituent Group d]
Substituent group d includes a halogen atom, a hydroxyl group, a mercapto group, a cyano group, a formyl group, an oxo group, a C _1-6 alkyl group, a C _3-10 cycloalkyl group, a C _1-6 alkoxy group, an amino group, a mono- A C _1-6 alkylamino group, a di-C _1-6 alkylamino group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a diazepanyl group and a formula —T ⁴ -T ⁵ (wherein T ⁴ is a carbonyl group) Or a sulfonyl group is meant.
T ⁵ is a C _1-6 alkyl group, a C _3-10 cycloalkyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a hydroxyl group, a C _1-6 alkoxy group, an amino group, a mono-C _1-6 alkylamino group or A di-C _1-6 alkylamino group is meant. ) Represents a group consisting of groups represented by
However, each group described in the substituent group d may have a hydroxyl group, a C _1-6 alkyl group, a di-C _1-6 alkylamino group, an azetidinyl group, or a pyrrolidinyl group.

[Significance of Substituent Group e]
The substituent group e means a methyl group, an ethyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, and a piperazinyl group.
However, each group described in the substituent group e may have a hydroxyl group, a methyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group, or a piperidinyl group.

[Significance of Substituent Group f]
The substituent group f means a methyl group, an ethyl group, an n-propyl group, an acetyl group, a dimethylamino group, a diethylamino group, an azetidinyl group, a pyrrolidinyl group, and a piperazinyl group.
However, each group described in the substituent group f may have a methyl group or a dimethylamino group.

[Significance of Substituent Group g]
Substituent group g includes dimethylamino group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, dimethylaminomethyl group, dimethylaminoethyl group, azetidin-1-ylmethyl group, pyrrolidin-1-ylmethyl group and piperidin-1- It means an ylmethyl group.
However, each group described in the substituent group g may have a methyl group or a dimethylamino group.

[Significance of Substituent Group g-1]
Substituent group g-1 is an azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, dimethylaminomethyl group, dimethylaminoethyl group, azetidin-1-ylmethyl group, pyrrolidin-1-ylmethyl group and piperidin-1-ylmethyl group Means.
However, each group described in the substituent group g-1 may have a methyl group or a dimethylamino group.

[Significance of Substituent Group g-2]
Substituent group g-2 means a hydroxyl group, a methoxy group, a hydroxymethyl group, and a dimethylaminoacetoxy group.

[Significance of Substituent Group h]
The substituent group h means a dimethylamino group, a diethylamino group, a dimethylaminoethyl group, a dimethylaminopropyl group, and a 1-methylazetidin-3-yl group.

[Significance of R ² and R ³ ]
R ² and R ³ represent a hydrogen atom.

で表される基の好適な例としては、式

で表される基または式

で表される基があげられる。 [Significance of R ⁴ , R ⁵ , R ⁶ and R ⁷ ]
R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a trifluoromethyl group, a C _1-6 alkyl group, a C _2-6 alkenyl group, C _{2. -6} alkynyl group, C _1-6 alkoxy group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, formula —CO—R ¹² (wherein R ¹² is hydrogen An atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group, a mono-C _1-6 alkylamino group or a di-C _1-6 alkylamino group). Means.
Preferable examples of R ⁴ , R ⁵ , R ⁶ and R ⁷ include a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a trifluoromethyl group.
More preferred examples of R ⁴ , R ⁵ , R ⁶ and R ⁷ include a hydrogen atom, a halogen atom or a C _1-6 alkyl group.
More preferable examples of R ⁴ , R ⁵ , R ⁶ and R ⁷ include a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group.
R ⁴ , R ⁵ , R ⁶ and R ⁷ are 1) when all are hydrogen atoms, 2) when all are substituents other than hydrogen atoms, 3) when they are substituents other than hydrogen atoms or hydrogen atoms Any of them may be used, but preferably 2 to ⁴ of R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen atoms.
The formula

As preferable examples of the group represented by the formula:

A group or formula represented by

The group represented by these is mention | raise | lifted.

[The significance of ^{R 8]}
R ⁸ means a hydrogen atom or a C _1-6 alkyl group.
A preferred example of R ⁸ is a hydrogen atom.

[Significance of R ⁹ ]
R ⁹ is a 3- to 10-membered non-aromatic heterocyclic group (provided that a nitrogen atom is necessarily contained in the atoms constituting the ring and a bond is out of the nitrogen atom) or a formula- A group represented by a group represented by NR ^11a R ^11b (wherein R ^11a and R ^11b have the same meanings as defined above).
However, R ⁹ may have a substituent selected from the substituent group a or the substituent group b.
Preferable examples of R ⁹ include mono-C _1-6 alkylamino group, mono-C _3-10 cycloalkylamino group, mono-C _6-10 arylamino group, mono-5-10 membered heteroarylamino Group or a mono-4 to 10-membered non-aromatic heterocyclic amino group (provided that R ⁹ may have a substituent selected from the substituent group a or the substituent group b). .
More preferable examples of R ⁹ include a mono-C _3-10 cycloalkylamino group or a mono-C _6-10 arylamino group (provided that R ⁹ represents the substituent group a or the substituent group). It may have a substituent selected from b).
More preferred examples of R ⁹ include a mono-C _3-10 cycloalkylamino group or a mono-C _6-10 arylamino group (wherein R ⁹ is a substituent selected from the following substituent group i) May be included.)
[Substituent group i]
A halogen atom, a trifluoromethyl group, a cyano group, a C _1-6 alkyl group and a C _1-6 alkoxy group;
Particularly preferred examples of R ⁹ include a cyclopentylamino group, a cyclohexylamino group, a cycloheptylamino group, and a phenylamino group (provided that R ⁹ has a substituent selected from the above substituent group i). May be.)
A most preferred example of R ⁹ is a phenylamino group which may have a substituent selected from the above substituent group i.

[Significance of n]
n means an integer of 1 to 2.
A preferred example of n is 1.

[Significance of X]
X is the formula —C (R ¹⁰ ) = (wherein R ¹⁰ is a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a formula ^(wherein, R ¹² means the the same meanings as defined.) -CO-R 12 means a group represented by.) refers to a group or a nitrogen atom represented by.
Preferable examples of X include a group represented by the formula —C (R ^10a ) = (wherein R ^10a represents a hydrogen atom, a halogen atom or a cyano group) or a nitrogen atom.
More preferred examples of X include a group represented by the formula —CH═ or a nitrogen atom.

As a preferable compound in the general formula (I), each aspect of the R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X and n in the compound is selected. And compounds in which they are arbitrarily combined.

Specific examples of the compound in the general formula (I) include the compounds exemplified below.
(1) N- (4-{[2-({[(1-ethylpiperidin-4-yl) (methyl) amino] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N'- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(2) N- (4-{[2-({[(1-ethylpiperidin-4-yl) (methyl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(3) N- {2-fluoro-4-[(2-{[(4-methyl-1,4-diaspan-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(4) N- (4-fluorophenyl) -N ′-{2-fluoro-4-[(2-{[(3-pyrrolidin-1-ylazetidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} cyclopropane-1,1-dicboxamide,
(5) N- {2-fluoro-4-[(2-{[(4-methylpiperazin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(6) N- [4-({2-[({4- [2- (dimethylamino) ethyl] -1,4-diazepan-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2 -Fluorphenyl] -N'-phenylcyclopropane-1,1-dicboxamide,
(7) N- (4-{[2-({[3- (dimethylamino) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(8) N- (4-{[2-({[3- (dimethylamino) azetinin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-(4-fluorophenyl) cyclopropane -1,1-dicarboxamide,
(9) N- (4-{[2-({[3- (dimethylamino) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N'-phenylcyclopropane-1 , 1-dicarboxamide,
(10) N- [2-fluoro-4-({2-[({methyl [1- (1-methylazetidin-3-yl) piperidin-4-yl] amino} carbonyl) amino] pyridin-4-yl} oxy) phenyl] -N′-phenylcyclopropane-1,1-dicboxamide,
(11) N- (2-fluoro-4-{[2-({[4- (1-methylazetidin-3-yl) piperazin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'-phenylcyclopropane-1,1-dicboxamide,
(12) N- (4-fluorophenyl) -N ′-(4-{[2-({[4- (1-methylazetidin-3-yl) piperazin-1-yl] carbonyl} amino) pyridin-4-yl ] Oxy} phenyl) cyclopropane-1,1-dicboxamide,
(13) N- (2-fluoro-4-{[2-({[(1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-(4 -Fluorphenyl) cyclopropane-1, 1-dicboxamide,
(14) N- {2-fluor-4--4-[(2-{[(4-hydroxy-1,4'-biperidin-1'-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl}- N′-phenylcyclopropane-1,1-dicboxamide,
(15) N- (4-{[2-({[{1- [3- (dimethylamino) propyl] piperidin-4-yl} (methyl) amino] carbonyl} amino) pyridin-4-yl] oxy}- 2-fluorophenyl) -N′-phenylcyclopropane-1,1-dicboxamide,
(16) N- (4-{[2-({[(3-azetidin-1-ylpropyl) (methyl) amino] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N'- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(17) N- (2-fluor-4--4-[[2-({[methyl (3-pyrrolidin-1-ylpropyl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(18) N- (4-{[2-({[[3- (dimethylamino) propyl] (methyl) amino] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N '-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(19) N- (2-fluoro-4-{[2-({[methyl (4-pyrrolidin-1-ylbutyl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N′-phenylcyclopropane -1,1-dicarboxamide,
(20) N- [2-fluoro-4-({2-[(morpholin-4-ylcarbonyl) amino] pyridin-4-yl} oxy) phenyl] -N '-(4-fluorophenyl) cyclopropane-1,1 -Dicarboxamide,
(21) N- [4-({2-[(azetidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N ′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide,
(22) N- (2-fluoro-4-{[2-({[methyl (3-morpholin-4-ylpropyl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(23) N- [2-fluoro-4-({2-[({methyl [3- (4-methylpiperazin-1-yl) propyl] amino} carbonyl) amino] pyridin-4-yl} oxy) phenyl] -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(24) N- (4-fluorophenyl) -N ′-[2-fluoro-4-({2-[(pyrrolidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) phenyl] cyclopropane-1,1 -Dicarboxamide,
(25) N- (2-fluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'-2 -Thienylcyclopropane-1,1-dicboxamide,
(26) N- (2-fluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'-1 , 3-thiazol-2-ylcyclopropane-1,1-dicboxamide,
(27) N- (2-fluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-( 5-methylisoxazol-3-yl) cyclopropane-1,1-dicboxamide,
(28) N- (2-fluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-( 3-methylisoxazol-5-yl) cyclopropane-1,1-dicboxamide,
(29) N- {2-fluor-4--4-[(2-{[(4-hydroxypiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(30) N- {2-fluor-4--4-[(2-{[(4-methoxypiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(31) N- {2-fluor-4--4-[(2-{[(3-hydroxyzetidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(32) N- {2-fluor-4--4-[(2-{[(3-methoxyzetidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(33) N- (2-fluoro-4-{[2-({[(2-methoxyethyl) (methyl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(34) N- (2-fluoro-4-{[2-({[4- (3-hydroxyzetidin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(35) N- (2-fluoro-4-{[2-({[methyl (tetrahydro-2H-pyran-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(36) N- (2-fluoro-4-{[2-({[methyl (1-methylpiperidin-3-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(37) N- [4-({2-[({3-[(dimethylamino) methyl] piperidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) phenyl] -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(38) N- [4-({2-[({3-[(dimethylamino) methyl] pyrrolidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N′- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(39) N- (2-fluor-4--4-[[2-({[methyl (1-methylpyrrolidin-3-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(40) N- {2-fluor-4--4-[(2-{[(3-hydroxypyrrolidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(41) N- {2-fluor-4--4-[(2-{[(3-methoxypyrrolidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(42) N- {4-[(2-{[(3,4-dihydroxypyrrolidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] -2-fluorophenyl} -N '-(4-fluorophenyl ) Cyclopropane-1,1-dicboxamide,
(43) N- {2-fluoro-4-[(2-{[(3-hydroxy-4-methoxypyrrolidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(44) N- {4-[(2-{[(3,4-dimethylpyrrolidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] -2-fluorophenyl} -N ′-(4-fluorophenyl) ) Cyclopropane-1,1-dicboxamide,
(45) N- {2-fluor-4--4-[(2-{[(3-hydroxypiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(46) N- {2-fluor-4--4-[(2-{[(3-methoxypiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide, and (47) N- (4-{[2-({[3- (dimethylamino) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2- Fluorophenyl) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicboxamide.

Specific examples of the compound represented by the general formula (I) include the compounds shown below.
(1) N- [4-({2-[({4- [2- (Dimethylamino) ethyl] piperazin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N '-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide,
(2) N- (2-Fluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(3) N- (4-Fluorophenyl) -N ′-{2-fluoro-4-[(2-{[(4-pyrrolidin-1-ylpiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} cyclopropane-1,1-dicboxamide,
(4) N- [4-({2-[({4-[(Dimethylamino) methyl] piperidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2-fluorphenyl] -N'- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(5) N- {4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] -2-fluorophenyl} -N ′-(4 -Fluorphenyl) cyclopropane-1, 1-dicboxamide,
(6) N- [4-({2-[({4- [3- (Dimethylamino) azetinin-1-yl] piperidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2- fluorphenyl] -N ′-(4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(7) N- (2-Fluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(8) N- (2-Fluoro-4-{[2-({[4- (1-methylpiperidin-4-yl) piperazin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(9) N- (2-Fluoro-4-{[2-({[4- (1-methylazetidin-3-yl) piperazin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(10) N- (4-{[2-({[4- (Dimethylamino) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(11) N- (4-{[2-({[4- (Azetidin-1-ylmethyl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(12) N- (4-Fluorophenyl) -N ′-(2-fluoro-4-{[2-({[4- (pyrrolidin-1-ylmethyl) piperidin-1-yl] carbonyl} amino) pyridin-4 -Yl] oxy} phenyl) cyclopropane-1,1-dicboxamide,
(13) N- (4-{[2-({[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(14) N- (4-{[2-({[(3R) -3- (Dimethylamino) pyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(15) N- (2-Fluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'-phenylcyclopropane -1,1-dicarboxamide,
(16) N- (2-Fluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'-phenylcyclopropane-1,1-dicboxamide,
(17) N- [4-({2-[({4- [3- (Dimethylamino) azetinin-1-yl] piperidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2- fluorphenyl] -N′-phenylcyclopropane-1,1-dicboxamide,
(18) N- (4-{[2-({[(1-Ethylpiperidin-4-yl) (methyl) amino] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N'- phenylcyclopropane-1,1-dicboxamide,
(19) N- [4-({2-[(Azetidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N ′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide,
(20) N- (4-Fluorophenyl) -N ′-[2-fluoro-4-({2-[(pyrrolidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) phenyl] cyclopropane-1,1 -Dicarboxamide,
(21) N- {2-Fluoro-4-[(2-{[(3-hydroxyzetidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(22) N- [4-({2-[(1,3′-Biacetidin-1′-ylcarbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N ′-(4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(23) N- (2-Fluoro-4-{[2-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4 -Fluorphenyl) cyclopropane-1, 1-dicboxamide,
(24) N- (4-{[2-({[3- (Dimethylamino) azetinin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(25) N- [4-({2-[({3-[(Dimethylamino) methyl] azetinin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N′- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(26) N- {2-Fluoro-4-[(2-{[(4-hydroxypiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(27) N- (2-Fluoro-4-{[2-({[4- (hydroxymethyl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4 -Fluorphenyl) cyclopropane-1, 1-dicboxamide,
(28) N- (2-Fluoro-4-{[2-({[(3R) -3-hydroxypyrrolin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(29) N- (2-Fluoro-4-{[2-({[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(30) N- [4-({2-[(Azetidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) -2,5-difluorophenyl] -N ′-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide,
(31) N- {2,5-Difluoro-4--4-[(2-{[(3-hydroxyzetidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(32) N- (2,5-Difluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(33) N- [2,5-Difluoro-4-({2-[({3-[(dimethylamino) methyl] azetinin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) phenyl]- N ′-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(34) N- (2,5-Difluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(35) N- {4-[(2-{[3- (Azetidin-1-ylmethyl) azetinin-1-ylcarbonyl] amino} pyridin-4-yl) oxy] -2,5-difluorophenyl} -N′- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(36) N- (2,5-Difluoro-4-{[2-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N′- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(37) N- {2,5-Difluoro-4--4-[(4-{[(3-hydroxyzetidin-1-yl) carbonyl] amino} pyrimidin-6-yl) oxy] phenyl} -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(38) N- [4-({4-[({3-[(Dimethylamino) methyl] azetinin-1-yl} carbonyl) amino] pyrimidin-6-yl} oxy) -2,5-difluorophenyl] -N '-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide,
(39) N- (2,5-Difluoro-4-{[4-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyrimidin-6-yl] oxy} phenyl) -N'- (4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(40) N- (2,5-Difluoro-4-{[4-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyrimidin-6-yl] oxy} phenyl) -N ' -(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(41) N- (2,5-Difluoro-4-{[4-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyrimidin-6-yl] oxy} phenyl) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicboxamide,
(42) N- (4-{[2-({[4- (Dimethylamino) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2,5-difluorophenyl) -N '-( 4-fluorphenyl) cyclopropane-1,1-dicboxamide,
(43) N- {2,5-Difluoro-4--4-[(2-{[(4-methylpiperazin-1-yl) carbonyl] amino} pyridin-4-yl] oxy} phenyl) -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(44) N- {2,5-Difluoro-4-[(2-{[(4-hydroxypiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′-(4- fluorphenyl) cyclopropane-1, 1-dicboxamide,
(45) N- {4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] oxy} -2,5-difluorophenyl} -N '-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide,
(46) N- (2,5-Difluoro-4-{[2-({[3- (2-dimethylaminoacetoxy) azetin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide,
(47) N- (2,5-Difluoro-4-{[2-({[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide, and (48) N- (2,5-Difluoro-4-{[2-({[(3R) -3-hydroxylidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicboxamide.

More preferred specific examples of the compound represented by the general formula (I) include the compounds shown below.
(1) N- (2-Fluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1, 1-dicboxamide
(2) N- [4-({2-[(azetidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N ′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide
(3) N- {2,5-Difluoro-4-[(2-{[(3-hydroxyzetidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′-(4- fluorphenyl) cyclopropane-1,1-dicboxamide
(4) N- (2,5-Difluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicboxamide
(5) N- (2,5-Difluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicboxamide
(6) N- (2,5-Difluoro-4-{[2-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'- (4-Fluorophenyl) cyclopropane-1,1-dicboxamide.

  The phrase “may have a substituent selected from the substituent group” means that it may have 1 to 3 substituents arbitrarily selected from the substituents described in the substituent group. Means good.

  The compound based on this invention can be manufactured based on description of the international publication 2007/023768 pamphlet.

[Pharmacological test example]
The hepatocyte growth factor receptor inhibitory activity, antitumor activity, angiogenesis inhibitory activity, and cancer metastasis suppressive activity of the compounds according to the present invention have been confirmed in WO 2007/023768. The action of the compound according to the present invention on esophageal cancer was evaluated according to the following method.

A list of abbreviations or terms used in the following pharmacological test examples is shown below.
<List of abbreviations>
FBS (Fetal bovine serum)

Pharmacological Test Example 1: Inhibitory action on human esophageal cancer cell proliferation Human esophageal cancer cells (OE19, OE21 and OE33) were purchased from Dainippon Sumitomo Pharma Co., Ltd. OE19, OE21 or OE33 was suspended in RPMI 1640 medium (purchased from Sigma) containing 10% FBS. The cell suspension (2 × 10 ⁴ cells / ml) was added to a 96-well plate for cell culture (purchased from FALCON, product number 353075) at 0.1 ml / well in a 5% CO ₂ incubator (37 ° C.). Incubated overnight. After culturing, 0.1 ml of a test substance diluted with RPMI 1640 medium containing 10% FBS was added to each well, and further cultured in a 5% CO ₂ incubator (37 ° C.) for 3 days. After culturing, 10 μl of Cell Counting Kit-8 (purchased from DOJINDO, product number 343-07623) was added to each well and incubated in a 5% CO ₂ incubator (37 ° C.) for about 2 hours. After the incubation, the measurement wavelength was 450 nm, the control wavelength was 660 nm, and the absorbance of each well was measured using a plate reader MTP-500 (manufactured by Corona Electric Co., Ltd.). The ratio (%) of the absorbance of each well to which the test substance was added to the absorbance of the well to which the test substance was not added was determined, and from this ratio, the concentration of the test substance necessary for inhibiting cell growth by 50% (IC ₅₀ ; μM). The results are shown in Table 1.

  The compound according to the present invention has an excellent HGFR inhibitory action and is useful as a composition for treating esophageal cancer.

Claims (20)

General formula

(In the formula, R ¹ is a 3- to 10-membered non-aromatic heterocyclic group (provided that a nitrogen atom is necessarily contained in the atoms constituting the ring and a bond is out of the nitrogen atom). ) Or formula —NR ^11a R ^11b (wherein R ^11a and R ^11b are the same or different and represent a hydrogen atom, a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, C _{3). A -10} cycloalkyl group, a C _6-10 aryl group, a 5-10 membered heteroaryl group or a 4-10 membered non-aromatic heterocyclic group, provided that R ^11a and R ^11b represent the following substituent group a Or you may have a substituent chosen from the following substituent group b.
[Substituent group a]
A halogen atom, a hydroxyl group, a mercapto group, a nitro group, a cyano group and an oxo group;
[Substituent group b]
C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-10 cycloalkyl group, C _6-10 aryl group, 5-10 membered heteroaryl group, 3-10 membered non-aromatic Group heterocyclic group, C _1-6 alkoxy group, C _3-6 alkenyloxy group, C _3-6 alkynyloxy group, C _3-10 cycloalkoxy group, C _6-10 aryloxy group, 5-10 membered hetero Aryloxy group, 4-10 membered non-aromatic heterocyclic oxy group, C _1-6 alkylthio group, C _3-6 alkenylthio group, C _3-6 alkynylthio group, C _3-10 cycloalkylthio group, C _{6-6 A 10} arylthio group, a 5-10 membered heteroarylthio group, a 4-10 membered non-aromatic heterocyclic thio group and the formula -T ¹ -T ² -T ³
(In the formula, T ¹ means a single bond or a C _1-6 alkylene group.
T ² is a carbonyl group, a sulfinyl group, a sulfonyl group, a group represented by the formula —C (═O) —O—, a group represented by the formula —O—C (═O) —, or a formula —SO ₂ —. A group represented by the formula O—, a group represented by the formula —O—SO ₂ —, a group represented by the formula —NR ^T1 —, a group represented by the formula —C (═O) —NR ^T1 —, a formula It means a group represented by —NR ^T1 —C (═O) —, a group represented by the formula —SO ₂ —NR ^T1 — or a group represented by the formula —NR ^T1 —SO ₂ —.
T ³ is a hydrogen atom, a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-10 cycloalkyl group, a C _6-10 aryl group, or a 5-10 membered heteroaryl group. Or means a 4- to 10-membered non-aromatic heterocyclic group.
R ^T1 means a hydrogen atom or a C _1-6 alkyl group. ), And each of the above groups may have a substituent selected from the following substituent group c.
[Substituent group c]
Halogen atom, hydroxyl group, mercapto group, nitro group, cyano group, oxo group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-10 cycloalkyl group, C _6-10 Aryl group, 5-10 membered heteroaryl group, 3-10 membered non-aromatic heterocyclic group, C _1-6 alkoxy group, C _1-6 alkylthio group, mono-C _1-6 alkylamino group and di-C _1-6 alkylamino group. ).
However, R ¹ may have a substituent selected from the substituent group a or the substituent group b.
R ² and R ³ represent a hydrogen atom.
R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a trifluoromethyl group, a C _1-6 alkyl group, a C _2-6 alkenyl group, C _{2. -6} alkynyl group, C _1-6 alkoxy group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, formula —CO—R ¹² (wherein R ¹² is hydrogen An atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group, a mono-C _1-6 alkylamino group or a di-C _1-6 alkylamino group). Means.
R ⁸ means a hydrogen atom or a C _1-6 alkyl group.
R ⁹ is a 3- to 10-membered non-aromatic heterocyclic group (provided that a nitrogen atom is necessarily contained in the atoms constituting the ring and a bond is out of the nitrogen atom) or a formula- A group represented by a group represented by NR ^11a R ^11b (wherein R ^11a and R ^11b have the same meanings as defined above).
However, R ⁹ may have a substituent selected from the substituent group a or the substituent group b.
n means an integer of 1 to 2.
X is the formula —C (R ¹⁰ ) = (wherein R ¹⁰ is a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a formula ^(wherein, R ¹² means the the same meanings as defined.) -CO-R 12 means a group represented by.) refers to a group or a nitrogen atom represented by. )
Or a salt thereof, or a hydrate thereof. R ¹ may have a substituent selected from the substituent group a or the substituent group b according to claim 1, and the 3- to 10-membered non-aromatic heterocyclic group (however, constituting a ring) 2. The composition for treating esophageal cancer according to claim 1, wherein the nitrogen atom is necessarily contained in the atom and the bond is out of the nitrogen atom). R ¹ may have a substituent selected from substituent group a or substituent group b according to claim 1.

(Wherein, a represents an integer of 1 to 4) or a substituent selected from substituent group a or substituent group b according to claim 1. Good expression

(In the formula, b represents an integer of 1 to 3. Z represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfonyl group, or a formula —NR ^Z — (wherein R ^Z represents a hydrogen atom or C _{1- The} composition for esophageal cancer treatment according to claim 1, which is a group represented by the formula: R ¹ may have a substituent selected from the following substituent group d, an azetidin-1-yl group, and may have a substituent selected from the following substituent group d A group, a piperidin-1-yl group optionally having a substituent selected from the following substituent group d, an azepan-1-yl group optionally having a substituent selected from the following substituent group d, A piperazin-1-yl group optionally having a substituent selected from the following substituent group d; a diazepan-1-yl group optionally having a substituent selected from the following substituent group d; A morpholin-4-yl group optionally having a substituent selected from the group d, a thiomorpholin-4-yl group optionally having a substituent selected from the following substituent group d, or the following substituent 1,1-di optionally having substituents selected from group d The composition for esophageal cancer treatment according to claim 1, which is an oxothiomorpholin-4-yl group.
[Substituent group d]
Halogen atom, hydroxyl group, mercapto group, cyano group, formyl group, oxo group, C _1-6 alkyl group, C _3-10 cycloalkyl group, C _1-6 alkoxy group, amino group, mono-C _1-6 alkylamino Group, di-C _1-6 alkylamino group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, diazepanyl group and formula -T ⁴ -T ⁵ (wherein T ⁴ means a carbonyl group or a sulfonyl group) T ⁵ is a C _1-6 alkyl group, a C _3-10 cycloalkyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a hydroxyl group, a C _1-6 alkoxy group, an amino group, or a mono-C _1-6 alkylamino group. or means a di _{-C 1-6} alkylamino group.) a group represented by the above each group, a hydroxyl _{group, C 1-6} alkyl, di -C _-6 alkylamino group may have a azetidinyl or pyrrolidinyl group. R ¹ may have a substituent selected from the following substituent group e, an azetidin-1-yl group, and may have a substituent selected from the following substituent group e A piperidin-1-yl group optionally having a substituent selected from the following substituent group e, a piperazin-1-yl group optionally having a substituent selected from the following substituent group e, A diazepan-1-yl group which may have a substituent selected from the following substituent group e or a morpholin-4-yl group which may have a substituent selected from the following substituent group e. Item 5. A composition for treating esophageal cancer according to Item 1.
[Substituent group e]
It consists of a methyl group, an ethyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group and a piperazinyl group, each of the above groups having a hydroxyl group, a methyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group or a piperidinyl group. May be. R ¹ may have a substituent selected from the following substituent group g, an azetidin-1-yl group, a pyrrolidin-1-yl group having a substituent selected from the following substituent group g, and the following substituent The composition for esophageal cancer treatment according to claim 1, which is a piperidin-1-yl group having a substituent selected from group g or a piperazin-1-yl group having a substituent selected from the following substituent group g.
[Substituent group g]
Dimethylamino group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, dimethylaminomethyl group, dimethylaminoethyl group, azetidin-1-ylmethyl group, pyrrolidin-1-ylmethyl group and piperidin-1-ylmethyl group, Each group may have a methyl group or a dimethylamino group. R ¹ is ^{(wherein, R 11a} and ^{R 11b,} the same meaning as ^{R 11a} and ^{R 11b} described in claim 1.) Formula ^-NR 11a ^{R 11b} claim a group represented by 2. A composition for treating esophageal cancer according to 1. R ¹ represents a formula —NR ^11c R ^11d (where R ^11c represents a hydrogen atom or a C _1-6 alkyl group. R ^11d represents a C _1-6 alkyl group or a formula

(Wherein c represents an integer of 1 to 3. Z ¹ represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfonyl group, or a formula —NR ^Z1 — (wherein R ^Z1 represents a hydrogen atom or C ₁ Means a _-6 alkyl group.) Means a group represented by). However, R ^11d may have a substituent selected from the substituent group a or the substituent group b described in claim 1. The composition for esophageal cancer treatment according to claim 1, wherein the composition is a group represented by the formula: R ¹ represents a formula —NR ^11e R ^11f (wherein R ^11e represents a hydrogen atom or a C _1-6 alkyl group. R ^11f represents a C _1-6 alkyl group, a pyrrolidin-3-yl group, a piperidine) It means a -3-yl group, a piperidin-4-yl group or a tetrahydropyran-4-yl group, provided that R ^11f has a substituent selected from the substituent group d described in claim 4. The composition for treating esophageal cancer according to claim 1, which is a group represented by: R ¹ represents a formula —NR ^11g R ^11h (wherein R ^11g represents a hydrogen atom or a methyl group. R ^11h represents an n-propyl group, an n-butyl group, a pyrrolidin-3-yl group, a piperidine- 3-yl group, piperidin-4-yl group, or tetrahydropyran-4-yl group, provided that R ^11h may have a substituent selected from the following substituent group f). The composition for treating esophageal cancer according to claim 1, which is a group to be treated.
[Substituent group f]
It consists of a methyl group, an ethyl group, an n-propyl group, an acetyl group, a dimethylamino group, a diethylamino group, an azetidinyl group, a pyrrolidinyl group, and a piperazinyl group, and each of the above groups may have a methyl group or a dimethylamino group. . R ¹ represents a formula —N (CH ₃ ) R ¹¹ⁱ (wherein R ¹¹ⁱ represents an n-propyl group, an n-butyl group, a pyrrolidin-3-yl group, or a piperidin-4-yl group, provided that The composition for treating esophageal cancer according to claim 1, wherein R ¹¹ⁱ has a substituent selected from the following substituent group h.
[Substituent group h]
A dimethylamino group, a diethylamino group, a dimethylaminoethyl group, a dimethylaminopropyl group and a 1-methylazetidin-3-yl group; R ¹ is a group represented by the formula —N (CH ₃ ) R ^11j (wherein R ^11j represents a 1-methylpiperidin-4-yl group or a 1-ethylpiperidin-4-yl group). The composition for treating esophageal cancer according to claim 1. The composition for treating esophageal cancer according to any one of claims 1 to 12, wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a halogen atom or a C _1-6 alkyl group. . R ⁸ is, esophageal cancer therapeutic compositions of any one of claims 1 to 13 is a hydrogen atom. 15. X is a group represented by the formula —C (R ^10a ) = (wherein R ^10a represents a hydrogen atom, a halogen atom or a cyano group). A composition for treating esophageal cancer.   X is a nitrogen atom, The composition for esophageal cancer treatment of any one of Claims 1-14.   The composition for esophageal cancer treatment according to any one of claims 1 to 16, wherein n is 1. R ⁹ is a mono-C _1-6 alkylamino group optionally having a substituent selected from the substituent group a or the substituent group b according to claim 1, and the substitution according to claim 1. The mono-C _3-10 cycloalkylamino group which may have a substituent selected from the group a or the substituent group b, the substituent group a or the substituent group b according to claim 1. A mono-C _6-10 arylamino group which may have a substituent, and a mono-5 which may have a substituent selected from the substituent group a or the substituent group b according to claim 1. A mono-4 to 10-membered non-aromatic heterocyclic amino group which may have a 10-membered heteroarylamino group or a substituent selected from the substituent group a or the substituent group b according to claim 1 The esophageal cancer according to any one of claims 1 to 17. Therapeutic composition. R ⁹ is a mono-C _3-10 cycloalkylamino group which may have a substituent selected from the substituent group a or the substituent group b according to claim 1, or according to claim 1. The composition for treating esophageal cancer according to any one of claims 1 to 17, which is a mono-C _6-10 arylamino group which may have a substituent selected from substituent group a or substituent group b. . The compound represented by the general formula (I) is:
(1) N- [4-({2-[({4- [2- (dimethylamino) ethyl] piperazin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(2) N- (2-fluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'- (4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(3) N- (4-Fluorophenyl) -N ′-{2-fluoro-4-[(2-{[(4-pyrrolidin-1-ylpiperidin-1-yl) carbonyl] amino} pyridine-4- Yl) oxy] phenyl} cyclopropane-1,1-dicarboxamide,
(4) N- [4-({2-[({4-[(Dimethylamino) methyl] piperidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(5) N- {4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] -2-fluorophenyl} -N′- (4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(6) N- [4-({2-[({4- [3- (dimethylamino) azetidin-1-yl] piperidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2 -Fluorophenyl] -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(7) N- (2-fluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl ) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(8) N- (2-Fluoro-4-{[2-({[4- (1-methylpiperidin-4-yl) piperazin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl ) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(9) N- (2-Fluoro-4-{[2-({[4- (1-methylazetidin-3-yl) piperazin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} Phenyl) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(10) N- (4-{[2-({[4- (Dimethylamino) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N ′-( 4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(11) N- (4-{[2-({[4- (azetidin-1-ylmethyl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(12) N- (4-Fluorophenyl) -N ′-(2-fluoro-4-{[2-({[4- (pyrrolidin-1-ylmethyl) piperidin-1-yl] carbonyl} amino) pyridine- 4-yl] oxy} phenyl) cyclopropane-1,1-dicarboxamide,
(13) N- (4-{[2-({[(3S) -3- (dimethylamino) pyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl)- N ′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(14) N- (4-{[2-({[(3R) -3- (dimethylamino) pyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl)- N ′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(15) N- (2-fluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'- Phenylcyclopropane-1,1-dicarboxamide,
(16) N- (2-fluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl ) —N′-phenylcyclopropane-1,1-dicarboxamide,
(17) N- [4-({2-[({4- [3- (dimethylamino) azetidin-1-yl] piperidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2 -Fluorophenyl] -N'-phenylcyclopropane-1,1-dicarboxamide,
(18) N- (4-{[2-({[(1-Ethylpiperidin-4-yl) (methyl) amino] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N '-Phenylcyclopropane-1,1-dicarboxamide,
(19) N- [4-({2-[(azetidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N ′-(4-fluorophenyl) cyclopropane- 1,1-dicarboxamide,
(20) N- (4-fluorophenyl) -N ′-[2-fluoro-4-({2-[(pyrrolidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) phenyl] cyclopropane- 1,1-dicarboxamide,
(21) N- {2-fluoro-4-[(2-{[(3-hydroxyazetidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′-(4- Fluorophenyl) cyclopropane-1,1-dicarboxamide,
(22) N- [4-({2-[(1,3′-Biazetidin-1′-ylcarbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N ′-(4- Fluorophenyl) cyclopropane-1,1-dicarboxamide,
(23) N- (2-Fluoro-4-{[2-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-( 4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(24) N- (4-{[2-({[3- (dimethylamino) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2-fluorophenyl) -N '-( 4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(25) N- [4-({2-[({3-[(Dimethylamino) methyl] azetidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) -2-fluorophenyl] -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(26) N- {2-fluoro-4-[(2-{[(4-hydroxypiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4-fluoro Phenyl) cyclopropane-1,1-dicarboxamide,
(27) N- (2-Fluoro-4-{[2-({[4- (hydroxymethyl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-( 4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(28) N- (2-fluoro-4-{[2-({[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'- (4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(29) N- (2-fluoro-4-{[2-({[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N'- (4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(30) N- [4-({2-[(azetidin-1-ylcarbonyl) amino] pyridin-4-yl} oxy) -2,5-difluorophenyl] -N ′-(4-fluorophenyl) cyclo Propane-1,1-dicarboxamide,
(31) N- {2,5-difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N ′-( 4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(32) N- (2,5-difluoro-4-{[2-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy } Phenyl) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(33) N- [2,5-difluoro-4-({2-[({3-[(dimethylamino) methyl] azetidin-1-yl} carbonyl) amino] pyridin-4-yl} oxy) phenyl] -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(34) N- (2,5-difluoro-4-{[2-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(35) N- {4-[(2-{[3- (azetidin-1-ylmethyl) azetidin-1-ylcarbonyl] amino} pyridin-4-yl) oxy] -2,5-difluorophenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(36) N- (2,5-difluoro-4-{[2-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N ' -(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(37) N- {2,5-difluoro-4-[(4-{[(3-hydroxyazetidin-1-yl) carbonyl] amino} pyrimidin-6-yl) oxy] phenyl} -N ′-( 4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(38) N- [4-({4-[({3-[(Dimethylamino) methyl] azetidin-1-yl} carbonyl) amino] pyrimidin-6-yl} oxy) -2,5-difluorophenyl] -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(39) N- (2,5-difluoro-4-{[4-({[3- (hydroxymethyl) azetidin-1-yl] carbonyl} amino) pyrimidin-6-yl] oxy} phenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(40) N- (2,5-difluoro-4-{[4-({[methyl (1-methylpiperidin-4-yl) amino] carbonyl} amino) pyrimidin-6-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(41) N- (2,5-difluoro-4-{[4-({[4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} amino) pyrimidin-6-yl] oxy } Phenyl) -N ′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(42) N- (4-{[2-({[4- (Dimethylamino) piperidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} -2,5-difluorophenyl) -N ′ -(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(43) N- {2,5-difluoro-4-[(2-{[(4-methylpiperazin-1-yl) carbonyl] amino} pyridin-4-yl] oxy} phenyl) -N ′-(4 -Fluorophenyl) cyclopropane-1,1-dicarboxamide,
(44) N- {2,5-difluoro-4-[(2-{[(4-hydroxypiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] phenyl} -N '-(4 -Fluorophenyl) cyclopropane-1,1-dicarboxamide,
(45) N- {4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl) carbonyl] amino} pyridin-4-yl) oxy] oxy} -2,5-difluorophenyl} -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(46) N- (2,5-difluoro-4-{[2-({[3- (2-dimethylaminoacetoxy) azetidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide,
(47) N- (2,5-difluoro-4-{[2-({[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-Fluorophenyl) cyclopropane-1,1-dicarboxamide or (48) N- (2,5-difluoro-4-{[2-({[(3R) -3-hydroxypyrrolidine-1- The composition for treating esophageal cancer according to claim 1, which is yl] carbonyl} amino) pyridin-4-yl] oxy} phenyl) -N '-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide.